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Clinical Trial Results:
An open-label, multi-center, roll-over study to assess long-term safety in patients with endogenous Cushing’s syndrome who have completed a prior Novartis-sponsored osilodrostat (LCI699) study and are judged by the investigator to benefit from continued treatment with osilodrostat

Summary
EudraCT number	2017-002840-34
Trial protocol	AT DE FR ES BG BE NL PL IT
Global end of trial date	16 Nov 2023

Results information
Results version number	v1(current)
This version publication date	01 Dec 2024
First version publication date	01 Dec 2024
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

CLCI699C2X01B

ISRCTN number

-

US NCT number

NCT03606408

WHO universal trial number (UTN)

-

Sponsor organisation name

Recordati AG

Sponsor organisation address

Uferstrasse 90, , Basel, Switzerland, 4057

Public contact

Clinical Trial Information Desk, Recordati AG, clinicaltrials.endocrinology@recordati.com

Scientific contact

Clinical Trial Information Desk, Recordati AG, clinicaltrials.endocrinology@recordati.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

29 Jul 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Nov 2023

Global end of trial reached?

Yes

Global end of trial date

16 Nov 2023

Was the trial ended prematurely?

No

Main objective of the trial

To evaluate long-term safety data based on frequency and severity of AEs/SAEs

Protection of trial subjects

Not Applicable

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

05 Oct 2018

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

1 Months

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 7

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Bulgaria: 3

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Italy: 13

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Brazil: 7

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

China: 10

Country: Number of subjects enrolled

Costa Rica: 3

Country: Number of subjects enrolled

India: 1

Country: Number of subjects enrolled

Japan: 2

Country: Number of subjects enrolled

Russian Federation: 5

Country: Number of subjects enrolled

Korea, Republic of: 6

Country: Number of subjects enrolled

Thailand: 7

Country: Number of subjects enrolled

Türkiye: 6

Country: Number of subjects enrolled

United States: 22

Worldwide total number of subjects

127

EEA total number of subjects

47

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

119

From 65 to 84 years

8

85 years and over

0

Subject disposition

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Recruitment details

-

Screening details

There was no screening period for the study, eligible patients were able to start study treatment as soon as they were enrolled. The first study visit was scheduled at the same time as the last study visit of the prior Novartis-sponsored study.

Period 1 title

baseline

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Not Applicable

baseline

Arm description

-

Arm type

Experimental

Investigational medicinal product name

Osilodrostat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients took the same Osilodrotat dose taken in he last day of previous Novartis study

Number of subjects in period 1	baseline
Started	127
Completed	127

Period 2 title

treatment

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Osilodrostat

Arm description

Patients were administered with osilodrostat, in the form of film-coated tablets for oral administration in 3 different strengths: 1 mg, 5 mg, and 10 mg. The patients received the same dose as they had been receiving in the prior Novartis-sponsored study. Dose modifications were allowed, up to a maximum of 30 mg twice a day

Arm type

Experimental

Investigational medicinal product name

Osilodrostat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients were administered with osilodrostat, in the form of film-coated tablets for oral administration in 3 different strengths: 1 mg, 5 mg, and 10 mg. The patients received the same dose as they had been receiving in the prior Novartis-sponsored study. Dose modifications were allowed, up to a maximum of 30 mg twice a day.

Number of subjects in period 2	Osilodrostat
Started	127
Completed	99
Not completed	28
Adverse event, serious fatal	1
Consent withdrawn by subject	7
Physician decision	4
Adverse event, non-fatal	13
New therapy for study indication	1
Lack of efficacy	2

Baseline characteristics

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Reporting group title

baseline

Reporting group description

-

Reporting group values	baseline	Total
Number of subjects	127	127
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	119	119
From 65-84 years	8	8
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	44.2 ( 12.39 )	-
Gender categorical
Units: Subjects
Female	95	95
Male	32	32

End points

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Reporting group title

baseline

Reporting group description

-

Reporting group title

Osilodrostat

Reporting group description

Patients were administered with osilodrostat, in the form of film-coated tablets for oral administration in 3 different strengths: 1 mg, 5 mg, and 10 mg. The patients received the same dose as they had been receiving in the prior Novartis-sponsored study. Dose modifications were allowed, up to a maximum of 30 mg twice a day

Primary: Number of participants with adverse/serious adverse events

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End point title

Number of participants with adverse/serious adverse events ^[1]

End point description

To evaluate long-term safety data with osilodrostat treatment (Frequency and severity of adverse events (AEs)/serious adverse events (SAEs))

End point type

Primary

End point timeframe

up to 5 years.

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: Descriptive statistics were used for all variables, as appropriate. Continuous variables were summarised by the number of observations, mean, standard deviation (SD), median, upper and lower quartiles (as applicable), minimum, and maximum. Categorical variables were summarised by the number of non-missing observations and percentages for each category. The baseline visit (W1D1) of this study corresponded to the end of treatment (EOT) visit in the respective prior Novartis-sponsored study.

End point values	baseline	Osilodrostat
Number of subjects analysed	127	127
Units: participants
number (not applicable)
adverse event	0	115
treatment related AEs	0	50
adverse events of CTCAE grade >3	0	34
Treatment-related AEs of CTCAE Grade ≥ 3	0	3
Serious adverse events	0	35
Treatment-related SAEs	0	4
Fatal SAEs	0	2
Treatment-related fatal SAEs	0	0
Adverse events leading to discontinuation	0	14
Adverse events leading to dose interruption or adj	0	56
Treatment-related AEs leading to dose interruption	0	35
Adverse events requiring additional therapy	0	94
Treatment-related AEs requiring additional therapy	0	17
Adverse events of special interest (AESIs)	0	51
Treatment-related AESIs	0	29
treatment related AEs leading to discontonuation	0	5

No statistical analyses for this end point

Secondary: Percentage of Patients With Clinical Benefit

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End point title

Percentage of Patients With Clinical Benefit

End point description

Proportion of patients with clinical benefit as assessed by the Investigator at scheduled visits based on medical check-up and lab values such as Urine Free Cortisol.

End point type

Secondary

End point timeframe

up to 5 years

End point values	baseline	Osilodrostat
Number of subjects analysed	127	127
Units: participants
number (not applicable)
week 1	0	127
week 12	0	122
week 24	0	119
week 36	0	114
week 48	0	103
week 96	0	744
week 144	0	52
end of treatment	0	99

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

up to 5 years

Adverse event reporting additional description

As the objective of the study was to evaluate the long-term safety of osilodrostat, the patients have been analysed all together, regardless the drug dosage. Two (1.6%) patients experienced SAEs with the outcome of death during the study; these occurred during the 30-day post-treatment follow-up period (before the Safety Follow-up). These deaths w

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

treatment

Reporting group description

-

Serious adverse events	treatment
Total subjects affected by serious adverse events
subjects affected / exposed	35 / 127 (27.56%)
number of deaths (all causes)	2
number of deaths resulting from adverse events	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACTH-producing pituitary tumour
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Pituitary tumour
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Pituitary tumour benign
subjects affected / exposed	3 / 127 (2.36%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Renal neoplasm
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Influenza like illness
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Psychiatric disorders
Acute stress disorder
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Product issues
Device dislocation
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
Hand fracture
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Humerus fracture
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Radius fracture
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Wrist fracture
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Nervous system disorders
Paralysis
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Eye disorders
Retinal vein thrombosis
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Diverticulitis
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Food poisoning
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Nausea
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Biliary dilatation
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Cholelithiasis
subjects affected / exposed	3 / 127 (2.36%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Renal colic
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	2 / 127 (1.57%)
occurrences causally related to treatment / all	2 / 2
deaths causally related to treatment / all	0 / 0
Pituitary-dependent Cushing's syndrome
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Musculoskeletal and connective tissue disorders
Flank pain
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
COVID-19
subjects affected / exposed	7 / 127 (5.51%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 2
Pneumonia
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0
deaths causally related to treatment / all	0 / 0

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

Non-serious adverse events	treatment
Total subjects affected by non serious adverse events
subjects affected / exposed	115 / 127 (90.55%)
Investigations
Cortisol free urine increased
subjects affected / exposed	13 / 127 (10.24%)
occurrences all number	0
SARS-CoV-2 test positive
subjects affected / exposed	13 / 127 (10.24%)
occurrences all number	0
Vascular disorders
Hypertension
subjects affected / exposed	11 / 127 (8.66%)
occurrences all number	0
Nervous system disorders
Dizziness
subjects affected / exposed	10 / 127 (7.87%)
occurrences all number	0
Headache
subjects affected / exposed	16 / 127 (12.60%)
occurrences all number	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	9 / 127 (7.09%)
occurrences all number	0
Blood corticotrophin increased
subjects affected / exposed	8 / 127 (6.30%)
occurrences all number	0
Fatigue
subjects affected / exposed	9 / 127 (7.09%)
occurrences all number	0
Pyrexia
subjects affected / exposed	8 / 127 (6.30%)
occurrences all number	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	9 / 127 (7.09%)
occurrences all number	0
Diarrhoea
subjects affected / exposed	13 / 127 (10.24%)
occurrences all number	0
nausea
subjects affected / exposed	14 / 127 (11.02%)
occurrences all number	0
Vomiting
subjects affected / exposed	9 / 127 (7.09%)
occurrences all number	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 127 (5.51%)
occurrences all number	0
Oropharyngeal pain
subjects affected / exposed	7 / 127 (5.51%)
occurrences all number	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	16 / 127 (12.60%)
occurrences all number	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	9 / 127 (7.09%)
occurrences all number	0
Back pain
subjects affected / exposed	11 / 127 (8.66%)
occurrences all number	0
Infections and infestations
COVID-19
subjects affected / exposed	29 / 127 (22.83%)
occurrences all number	0
Influenza
subjects affected / exposed	11 / 127 (8.66%)
occurrences all number	0
Nasopharyngitis
subjects affected / exposed	12 / 127 (9.45%)
occurrences all number	0
Upper respiratory tract infection
subjects affected / exposed	10 / 127 (7.87%)
occurrences all number	0
Urinary tract infection
subjects affected / exposed	7 / 127 (5.51%)
occurrences all number	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 127 (7.09%)
occurrences all number	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

16 Jul 2021

Implementation of additional safety assessments as detailed in protocol amendment 1. Introduction of interim analysis for safety.

14 Apr 2023

Implementation of protocol amendment 2. Identification of the data from parent studies to complete baseline visits (W1D1). Deletion of outputs for Sections 10, 11, and 12.

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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The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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