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Clinical Trial Results:
A Single-Dose Open-Label Study of XOMA 358 in Patients with Congenital Hyperinsulinism (CHI)

Summary
EudraCT number	2015-002847-32
Trial protocol	GB
Global end of trial date	13 Jan 2017

Results information
Results version number	v1(current)
This version publication date	04 May 2018
First version publication date	04 May 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

X358602

ISRCTN number

US NCT number

NCT02604485

WHO universal trial number (UTN)

Sponsor organisation name

Xoma (US) LLC

Sponsor organisation address

220 Powell Street, Suite 310, Emeryville, United States, CA 94608

Public contact

Kirk Johnson, Xoma (US) LLC, +1 510 204 7439, Kirk.Johnson@xoma.com

Scientific contact

Kirk Johnson, Xoma (US) LLC, +1 510 204 7439, Kirk.Johnson@xoma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Nov 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Jan 2017

Global end of trial reached?

Yes

Global end of trial date

13 Jan 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety , pharmacokinetics and pharmacodynamics of a single dose of XOMA 358 in patients with hypoglycaemia associated with congenital hyperinsulinism.

Protection of trial subjects

This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable local regulatory requirements. Patients were assured that they could withdraw from the study at any time without jeopardizing their medical care. Close monitoring of all subjects was adhered to throughout the trial conduct.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

United States: 7

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects ≥12 years (UK) or at ≥18 years (US) with a clinical diagnosis of CHI, who could be safely washed out of background CHI medications and met all inclusion/exclusion criteria were enrolled. There were two screen failures. The hypoglycemia inclusion criteria was modified during the study via protocol amendments (see More Information section).

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

X358 1 mg/kg

Arm description

Single dose X358 1 mg/kg

Arm type

Experimental

Investigational medicinal product name

X358

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Single 1 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion.

X358 3 mg/kg

Arm description

Single dose X358 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

X358

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Single 3 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion

X358 6 mg/kg

Arm description

Single dose X358 6 mg/kg

Arm type

Experimental

Investigational medicinal product name

X358

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Single 6 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion

X358 9 mg/kg

Arm description

Single dose X358 9 mg/kg

Arm type

Experimental

Investigational medicinal product name

X358

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Single 9 mg/kg IV dose of X358 as an infusion over 30 minutes on 1 occasion.

Number of subjects in period 1	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Started	2	3	4	1
Completed	2	3	4	1

Baseline characteristics

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Reporting group title

X358 1 mg/kg

Reporting group description

Single dose X358 1 mg/kg

Reporting group title

X358 3 mg/kg

Reporting group description

Single dose X358 3 mg/kg

Reporting group title

X358 6 mg/kg

Reporting group description

Single dose X358 6 mg/kg

Reporting group title

X358 9 mg/kg

Reporting group description

Single dose X358 9 mg/kg

Reporting group values	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg	Total
Number of subjects	2	3	4	1	10
Age categorical
Units: Subjects
Adolescents (12-17 years)	0	1	1	0	2
Adults (18-64 years)	2	2	3	1	8
Age continuous
Units: years
median (standard deviation)	22.5 ± 2.12	23.7 ± 11.50	20.8 ± 7.63	32.0 ± 0	-
Gender categorical
Units: Subjects
Female	2	0	3	0	5
Male	0	3	1	1	5
K(ATP) mutation
Units: Subjects
Yes	0	2	3	0	5
No	2	1	1	1	5

End points

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Reporting group title

X358 1 mg/kg

Reporting group description

Single dose X358 1 mg/kg

Reporting group title

X358 3 mg/kg

Reporting group description

Single dose X358 3 mg/kg

Reporting group title

X358 6 mg/kg

Reporting group description

Single dose X358 6 mg/kg

Reporting group title

X358 9 mg/kg

Reporting group description

Single dose X358 9 mg/kg

Subject analysis set title

Subgroup Analysis 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with duration of hypoglycemia < 70 mg/dL >= 120 minutes at Baseline (non-fast). Subjects in 1 mg/kg cohort are excluded

Subject analysis set title

Subgroup Analysis 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with average duration of hypoglycemia of < 70 mg/dL >= 120 minutes at Baseline (4-5 days). Subjects in 1 mg/kg cohort are excluded.

Subject analysis set title

Subgroup Analysis 3

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects excluding 1 mg/kg cohort

Primary: Fasting glucose, insulin, C-peptide, ketones, free fatty acids

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End point title

Fasting glucose, insulin, C-peptide, ketones, free fatty acids ^[1]

End point description

End of fast values for glucose, insulin, C-peptide, ketones, free fatty acids are presented for Baseline (Day -5) and post dose value (Day 3, 5 or 11). The fast began after the consumption of dinner on the night before each listed day and continued for 24 hours or until blood glucose dropped to < 60 mg/dL or until other parameters were met Blood glucose and ketones were measured with a bedside glucometer, every 3 hours until blood glucose was < 70 mg/dL and every hour until blood glucose was < 60 mg/dL. The fast ended when set criteria was met: Pre-determined fasting time of 24 hours was reached, or Blood glucose was less than 60 mg/dL, or bedside ketones was > 2.5 mmol/L on 2 separate readings, or patient was symptomatic.

End point type

Primary

End point timeframe

Day -11 prior to dosing and post dose up to Day 11

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.

End point values	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Number of subjects analysed	1	3	4	1
Units: mg/dL; mIU/L; ng/mL; mmol/L; mEq/L
arithmetic mean (standard deviation)
Glucose; Baseline	74.0 ± 0	68.3 ± 5.51	67.8 ± 4.72	74.0 ± 0
Glucose; post-dose	79.0 ± 0	62.0 ± 0	67.5 ± 3.42	52.0 ± 0
insulin; Baseline	9.30 ± 0	4.23 ± 3.465	7.85 ± 1.353	9.90 ± 0
insulin; post-dose	52.40 ± 0	9.50 ± 0	69.95 ± 26.831	51.00 ± 0
C-peptide; Baseline	1.200 ± 0	0.663 ± 0.3667	1.203 ± 0.1841	1.320 ± 0
C-peptide; post-dose	2.090 ± 0	0.690 ± 0	1.568 ± 0.5881	1.360 ± 0
ketones; Baseline	0.540 ± 0	0.480 ± 0.3659	0.255 ± 0.0929	0.090 ± 0
ketones; post-dose	0.100 ± 0	1.410 ± 0	0.625 ± 0.3516	0.060 ± 0
free fatty acids; Baseline	0.90 ± 0	1.10 ± 0.400	0.88 ± 0.150	0.20 ± 0
free fatty acids; post-dose	0.40 ± 0	2.10 ± 0	1.13 ± 0.538	0.20 ± 0

No statistical analyses for this end point

Primary: Glucose area under the curve for each day (AUC24)

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End point title

Glucose area under the curve for each day (AUC24) ^[2]

End point description

Glucose area under the curve for each day (AUC24) for non-provocation days (patient did not have OGTT, protein or fasting challenges) are presented. No statistical data is included for patients in the 1 mg/kg group because both patients received diazoxide on Day 5.

End point type

Primary

End point timeframe

Glucose was followed via the continuous glucose monitor from Baseline (Day -6 to Day -1 prior to dosing) until post dose Day 29.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.

End point values	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Number of subjects analysed	2	3	4	1
Units: mg/dL*hr
arithmetic mean (standard deviation)
Day -2	2011.95 ± 173.178	2596.56 ± 353.453	2400.8 ± 401.154	1475.15 ± 0
Day -1	1906.97 ± 171.307	2588.14 ± 356.522	2234.17 ± 578.298	1513.05 ± 0
Day 1	2017.87 ± 108.686	2816.83 ± 619.072	2708.45 ± 165.641	1685.62 ± 0
Day 2	2267.18 ± 819.726	3017.17 ± 1190.837	3033.67 ± 234.912	1959.78 ± 0
Day 6	0 ± 0	2690.68 ± 598.16	2819.47 ± 575.821	1802.8 ± 0
Day 7	0 ± 0	2511.89 ± 564.422	2579.3 ± 792.292	1869.84 ± 0
Day 8	0 ± 0	2599.48 ± 469.251	2964.46 ± 216.42	1881.66 ± 0
Day 9	0 ± 0	2633.45 ± 725.526	2977.29 ± 336.804	1802.72 ± 0
Day 10	0 ± 0	2635.97 ± 571.989	2954.02 ± 375.741	2101.95 ± 0
Day 15	0 ± 0	2187.55 ± 103.928	2828.65 ± 182.06	0 ± 0
Day 29	0 ± 0	1237.89 ± 1578.544	1185.99 ± 45.871	0 ± 0

No statistical analyses for this end point

Primary: Concomitant treatment/medications used during rescue

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End point title

Concomitant treatment/medications used during rescue ^[3]

End point description

Rescue medication taken by subjects for hypoglycaemia during the study is presented.

End point type

Primary

End point timeframe

Concomitant treatment used during rescue were reported from Baseline until the end of the study.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.

End point values	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Number of subjects analysed	2	3	4	1
Units: Number of subjects rescued by medication
Number of subjects rescued by medication	2	1	0	1

No statistical analyses for this end point

Primary: Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL

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End point title

Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL ^[4]

End point description

The number of hypoglycemic episodes ( < 70 mg/dL, <60 mg/dL, and <50 mg/dL) per day was reported over each 24-hour day and summarised herein for Baseline and post-dose Day 1 to 12, grouped by day Non-Provocation Days are Days -2, -1, 1 (dosing day), 2, 6 through 10, 15 and 29. The protein challenge was performed 4 hours after the breakfast time on Day -4 and Day 4. If the patient did not demonstrate hypoglycemia during the screening fast and demonstrated hypoglycemia during the Day -4 protein challenge, then additional protein challenges occurred on Days -3, 3, 5 and 11 and the fasts were not performed. * Non-provocation days. An instance of hypoglycemia started when there were 3 consecutive measurements within a 15 minute window that were less than the threshold value. The duration was the sum of the total time the patient was in the specified threshold.

End point type

Primary

End point timeframe

Glucose was followed via the continuous glucose monitor from Baseline (Day -6 to Day -1 prior to dosing) until post dose Day 29.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.

End point values	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Number of subjects analysed	2 ^[5]	3	4	1
Units: Hypoglycemia
geometric mean (standard deviation)
Threshold < 50 mg/dL, Day -2 & Day -1	0.25 ± 0.354	0.17 ± 0.289	0.13 ± 0.250	4.50 ± 0
Threshold < 50 mg/dL, Day 1	1.00 ± 1.414	0.00 ± 0.000	0.00 ± 0.000	7.00 ± 0
Threshold < 50 mg/dL, Day 2 & Day 6*	0.50 ± 0.707	0.00 ± 0.000	0.50 ± 0.408	5.00 ± 0
Threshold < 50 mg/dL, Day -4 & Day -1	0.25 ± 0.354	0.00 ± 0.000	0.13 ± 0.250	4.50 ± 0
Threshold < 50 mg/dL, Day 2 to Day 12	1.50 ± 1.650	0.36 ± 0.315	0.43 ± 0.155	4.55 ± 0
Threshold < 60 mg/dL, Day -2 & Day -1	1.75 ± 0.354	0.17 ± 0.289	0.75 ± 0.500	6.00 ± 0
Threshold < 60 mg/dL, Day 1	2.50 ± 2.121	0.00 ± 0.000	0.75 ± 0.957	8.00 ± 0
Threshold < 60 mg/dL, Day 2 & Day 6*	1.50 ± 2.121	0.33 ± 0.577	0.63 ± 0.250	6.50 ± 0
Threshold < 60 mg/dL, Day -4 & Day -1	2.50 ± 0.707	0.00 ± 0.000	0.88 ± 0.854	7.50 ± 0
Threshold < 60 mg/dL, Day 2 to Day 12	2.50 ± 3.064	0.61 ± 0.410	0.84 ± 0.114	5.64 ± 0
Threshold < 70 mg/dL, Day -2 & Day -1	4.50 ± 2.828	0.50 ± 0.000	1.75 ± 1.190	7.50 ± 0
Threshold < 70 mg/dL, Day 1	4.00 ± 1.414	1.00 ± 1.000	1.75 ± 0.500	4.00 ± 0
Threshold < 70 mg/dL, Day 2 & Day 6*	3.50 ± 4.590	1.50 ± 1.732	1.25 ± 0.645	8.00 ± 0
Threshold < 70 mg/dL, Day -4 & Day -1	3.75 ± 2.475	0.50 ± 0.500	1.25 ± 0.957	7.50 ± 0
Threshold < 70 mg/dL, Day 2 to Day 12	3.33 ± 2.828	1.42 ± 0.584	1.77 ± 0.436	6.36 ± 0

Notes
[5] - Both patients received Diazoxide on Day 5. Data collected Day 5 onwards are excluded from analysis

No statistical analyses for this end point

Primary: Average time per day of blood glucose < 70 mg/dL

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End point title

Average time per day of blood glucose < 70 mg/dL ^[6]

End point description

Average time per day of blood glucose < 70 mg/dL was reported over each 24-hour day and is summarised herein for Baseline values collected during the Screening period and Days 1 to D12 post dose, grouped by day Non-Provocation Days are Days -2, -1, 1 (dosing day), 2, 6 through 10, 15 and 29. The protein challenge was performed 4 hours after the breakfast time on Day -4 and Day 4. If the patient did not demonstrate hypoglycemia during the screening fast and demonstrated hypoglycemia during the Day -4 protein challenge, then additional protein challenges occurred on Days -3, 3, 5 and 11 and the fasts were not performed. * Non-provocation days.

End point type

Primary

End point timeframe

Glucose was followed via the continuous glucose monitor from Baseline (Day -6 to Day -1 prior to dosing) until post dose Day 29.

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.

End point values	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Number of subjects analysed	2	3	4	1
Units: minutes
arithmetic mean (standard deviation)
Day -2 & Day -1	303.75 ± 132.583	22.50 ± 18.028	105.00 ± 47.697	920.00 ± 0
Day 1	290.00 ± 134.350	71.67 ± 67.885	115.00 ± 41.833	905.00 ± 0
Day 2 & Day 6*	375.00 ± 494.975	109.17 ± 163.274	80.00 ± 50.662	652.50 ± 0
Day -4 & Day -1	318.75 ± 164.402	15.00 ± 10.000	96.88 ± 56.361	1042.50 ± 0
Day 2 to Day 12	464.17 ± 555.079	128.48 ± 119.190	130.57 ± 43.229	608.18 ± 0

No statistical analyses for this end point

Primary: Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA)

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End point title

Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA) ^[7] ^[8]

End point description

Protein challenge measurements were conducted prior to dosing (Day -4) and post dose (Day4) for glucose, insulin, C-peptide, ketones and free fatty acids. The protein challenge was performed 4 hours after the breakfast time on Day -4 and Day 4. Bedside glucose and serum PD blood draws took every 30 minutes during the protein challenge procedure, until the rescue criteria were met.Time-matched Day 4 change from Baseline (most recent, non-missing protein profile conducted during Screening period) is presented.

End point type

Primary

End point timeframe

Day -11 prior to dosing and post dose up to Day 11

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the small sample size, only a descriptive analysis and documentation of data listings of this endpoint was specified.

End point values	X358 3 mg/kg	X358 6 mg/kg
Number of subjects analysed	1	3
Units: mg/dL; mIU/L; ng/mL; mmol/L; mEq/L
arithmetic mean (standard deviation)
Glucose; Day 4; 0 hr before start of provocation	15.00 ± 0	20.33 ± 75.182
Glucose; Day 4; 30 minutes after provocation	4.00 ± 0	11.00 ± 13.115
insulin; Day 4; 0 hr before start of provocation	19.300 ± 0	256.133 ± 239.5830
insulin; Day 4; 30 minutes after provocation	36.600 ± 0	300.233 ± 218.3129
C-peptide; Day 4; 0 hr before start of provocation	0.6000 ± 0	0.3700 ± 2.22178
C-peptide; Day 4; 30 minutes after provocation	0.2000 ± 0	0.2200 ± 1.54793
ketones; Day 4; 0 hr before start of provocation	0.3200 ± 0	0.0133 ± 0.02517
ketones; Day 4; 30 minutes after provocation	0 ± 0	0 ± 0
FFA; Day 4; 0 hr before start of provocation	0.600 ± 0	0.167 ± 0.3055
FFA; Day 4; 30 minutes after provocation	0 ± 0	0 ± 0

No statistical analyses for this end point

Post-hoc: Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)

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End point title

Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)

End point description

Percentage change in glucose measurements (mg/dL) via CGM over 24 hours on non-fast Days 1-7 and 8-12 versus Baseline glucose values for non-fast days (Day -5 to Day -1 where 24 hour CGM is recorded) is presented. Subjects in 1 mg/kg cohort are excluded from this analysis

End point type

Post-hoc

End point timeframe

Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.

End point values	Subgroup Analysis 1
Number of subjects analysed	3
Units: Percent Change from baseline (non-fast)
median (full range (min-max))
Days 1-7 (non-fast)	14.079 (5.47 to 22.10)
Days 8-12 (non-fast)	10.887 (9.37 to 27.07)

No statistical analyses for this end point

Post-hoc: Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

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End point title

Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

End point description

Percentage change in glucose measurements (mg/dL) via CGMS over 24 hours on Days 1-8 versus Baseline (4-5 days) is presented.

End point type

Post-hoc

End point timeframe

Glucose was followed via the continuous glucose monitor from check in (5 days prior to dosing) until Day 29 post dose.

End point values	Subgroup Analysis 2
Number of subjects analysed
Units: Percent Change from baseline
median (full range (min-max))
Days 1-8	11.181 (5.98 to 21.74)

No statistical analyses for this end point

Post-hoc: Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

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End point title

Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

End point description

The change in fasting blood glucose (mg/dL) on Days 4 and 6 versus Baseline ( 2-days; Day -2 and Day -1) is presented.

End point type

Post-hoc

End point timeframe

Baseline (Day -2) to Day 6

End point values	Subgroup Analysis 3
Number of subjects analysed	8
Units: Change from baseline (2-days)
median (full range (min-max))
Days 4 and 6	9.255 (-7.50 to 24.50)

No statistical analyses for this end point

Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

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End point title

Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

End point description

The change in fasting blood glucose (mg/dL) on Days 4 and 6 versus Baseline (average of fasting blood glucose on Day -2, Day -1 and Day 1 pre-dose) is presented

End point type

Post-hoc

End point timeframe

Baseline (Day -2) to to Day 6

End point values	Subgroup Analysis 3
Number of subjects analysed	8
Units: Change from baseline (3-days)
median (full range (min-max))
Days 4 and 6	-3.333 (-13.51 to 14.50)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event data were to be collected throughout the study beginning at the time the patient had signed the ICF

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

X358 1 mg/kg

Reporting group description

Single dose X358 1 mg/kg

Reporting group title

X358 3 mg/kg

Reporting group description

Single dose X358 3 mg/kg

Reporting group title

X358 6 mg/kg

Reporting group description

Single dose X358 6 mg/kg

Reporting group title

X358 9 mg/kg

Reporting group description

Single dose X358 9 mg/kg

Serious adverse events	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Nervous system disorders
Myoclonus
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Cold sweat
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	X358 1 mg/kg	X358 3 mg/kg	X358 6 mg/kg	X358 9 mg/kg
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 2 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	1 / 1 (100.00%)
Vascular disorders
Hypotension
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Dizziness
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Thrombophlebitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Catheter site pain
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Catheter site related reaction
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 1 (100.00%)
occurrences all number	0	0	1	1
Feeling hot
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0
Infusion site induration
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Lethargy
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Cough
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Upper respiratory tract congestion
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Nervousness
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Investigations
Body temperature increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Injection site bruising
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Injection site pain
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	2 / 2 (100.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0	0
Nervous system disorders
Depressed level of consciousness
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Dizziness
subjects affected / exposed	1 / 2 (50.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	1 / 1 (100.00%)
occurrences all number	1	3	1	1
Headache
subjects affected / exposed	2 / 2 (100.00%)	3 / 3 (100.00%)	3 / 4 (75.00%)	1 / 1 (100.00%)
occurrences all number	5	4	9	4
Lethargy
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Myoclonus
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Paraesthesia
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	1	2	0
Vision blurred
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Mental impairment
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Somnolence
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	1	0	2
Eye disorders
Vision blurred
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0
Abdominal pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0
Nausea
subjects affected / exposed	2 / 2 (100.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	2	0	0
Vomiting
subjects affected / exposed	1 / 2 (50.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	0 / 1 (0.00%)
occurrences all number	1	1	2	0
Dyspepsia
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Hypoaesthesia oral
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Paraesthesia oral
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	0
Skin and subcutaneous tissue disorders
Cold sweat
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	2
Skin irritation
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Hyperhidrosis
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	1
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0
Pharyngitis
subjects affected / exposed	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2015

The amendment includes the following substantial changes:The scope of data to be reviewed by the DSRC before additional patients exposure or and changing the dose level was increased from Day 12 to all available data through Day 29.Two different Screening schedule options (Option A and Option B) were added to accommodate different availability and convenience needs of individual patients. The Schedules of Events were changed for logistic efficiency or to collect additional safety and drug characterization data.

12 Aug 2015

The amendment includes the following substantial changes: Protocol sections referring to pregnancy were clarified.

08 Dec 2015

The amendment includes the following substantial changes:A final safety follow-up visit, beyond Day 43, was added at Day 105 and collection of blood samples for hematology, chemistry, and urinalysis panels was added at Day 43. Subject inclusion criteria was modified to remove weight ≤ 90 kg at Screening to allow for the inclusion of patients who had a clinically meaningful decrease in blood glucose with symptoms during hypoglycaemia inducing procedures. If a patient did not demonstrate blood glucose values < 60 mg/dL during the Screening fast, yet demonstrated blood glucose values < 60 mg/dL during the Day -4 Protein Challenge, then a Protein Challenge was performed in lieu of a monitored fast on Days -3, 3, 5, and 11.

22 Feb 2016

The amendment includes the following substantial changes: The dose level for Cohort B was confirmed at 3 mg/kg, by recommendation of the DSRC and patients were permitted to participate in more than 1 cohort.

26 May 2016

The amendment includes the following substantial changes: The OGTT was omitted throughout the protocol. A third cohort, “Cohort C,” was added at a dose level of 6 mg/kg, and the resulting sample size was increased to up to a total of approximately 18 patients.An optional inpatient hypoglycemia provocation test (fasting procedure OR Protein Challenge procedure) was added at Day 22

26 Aug 2016

The amendment includes the following substantial changes: The hypoglycemia inclusion criterion was changed by replacing the required decrease in glucose levels during provocation with a required duration of decreased glucose levels as measured by CGM over a fixed period of time without provocation. The exclusion criterion “Use of any long-acting somatostatin analogs or glucose-affecting medications that require > 72-hour washout” was deleted. Screening options “A” and “B” were replaced with a single screening and Baseline schedule, and the Protein Challenge provocations have been omitted from the protocol. Cohort D with a single dose at 9 mg/kg X358 was added. Outcome measures were added for duration of hypoglycemia and number of episodes at relevant glucose levels.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Single-Dose Open-Label Study of XOMA 358 in Patients with Congenital Hyperinsulinism (CHI)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Fasting glucose, insulin, C-peptide, ketones, free fatty acids

Primary: Fasting glucose, insulin, C-peptide, ketones, free fatty acids

Primary: Glucose area under the curve for each day (AUC24)

Primary: Glucose area under the curve for each day (AUC24)

Primary: Concomitant treatment/medications used during rescue

Primary: Concomitant treatment/medications used during rescue

Primary: Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL

Primary: Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL

Primary: Average time per day of blood glucose < 70 mg/dL

Primary: Average time per day of blood glucose < 70 mg/dL

Primary: Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA)

Primary: Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA)

Post-hoc: Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)

Post-hoc: Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)

Post-hoc: Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

Post-hoc: Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

Post-hoc: Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

Post-hoc: Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Finland
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Hungary
Iceland
Ireland
Italy
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United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Single-Dose Open-Label Study of XOMA 358 in Patients with Congenital Hyperinsulinism (CHI)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Fasting glucose, insulin, C-peptide, ketones, free fatty acids

Primary: Fasting glucose, insulin, C-peptide, ketones, free fatty acids

Primary: Glucose area under the curve for each day (AUC24)

Primary: Glucose area under the curve for each day (AUC24)

Primary: Concomitant treatment/medications used during rescue

Primary: Concomitant treatment/medications used during rescue

Primary: Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL

Primary: Number of hypoglycemic events per day with glucose < 70 mg/dL, <60 mg/dL, and <50 mg/dL

Primary: Average time per day of blood glucose < 70 mg/dL

Primary: Average time per day of blood glucose < 70 mg/dL

Primary: Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA)

Primary: Postprandial glucose, insulin, C-peptide, ketones and free fatty acids (FFA)

Post-hoc: Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)

Post-hoc: Subgroup Analysis: Glucose Non-fast days 1-7 and 8-12 vs. Baseline (nonfast)

Post-hoc: Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

Post-hoc: Subgroup Analysis: Glucose Days 1-8 vs. Baseline (4-5 Days)

Post-hoc: Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

Post-hoc: Fasting Blood Glucose -Days 4 and 6 vs. Baseline (2- days)

Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

Post-hoc: Subgroup Analysis: Fasting Blood Glucose- Days 4 and 6 vs. Baseline (3- days)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Single-Dose Open-Label Study of XOMA 358 in Patients with Congenital Hyperinsulinism (CHI)