Clinical Trial Results:
An Open-label Study to Evaluate Efficacy and Safety of Long-term Treatment with ACH-0144471 in Patients with PNH who Completed Clinical Study ACH471-100
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Summary
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EudraCT number |
2017-000665-79 |
Trial protocol |
GB IT |
Global end of trial date |
03 Jan 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jan 2023
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First version publication date |
06 Jan 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ACH471 103
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03181633 | ||
WHO universal trial number (UTN) |
U1111-1196-0653 | ||
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Sponsors
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Sponsor organisation name |
Alexion Pharmaceuticals, Inc.
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Sponsor organisation address |
Alexion Pharmaceuticals, Inc., 100 College Street, United States, 06510
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Public contact |
Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 7 87148158, clinicaltrials.eu@alexion.com
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Scientific contact |
Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +33 7 87148158, clinicaltrials.eu@alexion.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Jan 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Jan 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Jan 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of the trial was to evaluate the safety and efficacy of long term therapy with danicopan in participants with paroxysmal nocturnal hemoglobinuria (PNH).
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Protection of trial subjects |
This study was conducted in accordance with the protocol and with the following:
• Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines
• Applicable International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines
• Applicable laws and regulations
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Jun 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
New Zealand: 5
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Korea, Republic of: 1
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Worldwide total number of subjects |
8
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EEA total number of subjects |
2
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
7
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||
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Pre-assignment
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Screening details |
Participants who demonstrated a clinical benefit from danicopan in the primary Study ACH471-100 (2016-002652-25), were eligible for long-term treatment with danicopan in this extension Study ACH471-103. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Danicopan | ||||||||||||||
Arm description |
Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 milligrams [mg] 3 times daily [TID]) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Danicopan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Danicopan was administered per dose and schedule specified in the arm description.
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Baseline characteristics reporting groups
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Reporting group title |
Danicopan
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Reporting group description |
Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 milligrams [mg] 3 times daily [TID]) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Danicopan
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Reporting group description |
Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 milligrams [mg] 3 times daily [TID]) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision. | ||
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End point title |
Change From Baseline in LDH Level at Week 25 [1] | ||||||||
End point description |
Change from Baseline = Serum LDH levels at Week 25 - Baseline Serum LDH levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for LDH level.
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End point type |
Primary
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End point timeframe |
Baseline, Week 25
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| 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Hgb Level in the Absence of RBC Transfusion at Week 25 [2] | ||||||||
End point description |
Change from Baseline = Hgb levels at Week 25 - Baseline Hgb levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Hgb level.
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End point type |
Primary
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End point timeframe |
Baseline, Week 25
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| 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Reticulocyte Counts at Week 25 [3] | ||||||||
End point description |
Change from Baseline = reticulocyte count at Week 25 - Baseline reticulocyte count. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for reticulocyte count.
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End point type |
Primary
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End point timeframe |
Baseline, Week 25
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| 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of RBC Units Transfused [4] | ||||||||
End point description |
Full analysis set included all enrolled and treated participants.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 169
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| 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of RBC Transfusion Instances [5] | ||||||||
End point description |
Full analysis set included all enrolled and treated participants.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 169
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| Notes [5] - 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in PNH Clone Size at Week 25 [6] | ||||||||
End point description |
The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Change from Baseline = PNH clone size at Week 25 - Baseline PNH clone size. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for PNH clone size.
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End point type |
Primary
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End point timeframe |
Baseline, Week 25
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| 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in AP Complement Functional Activity at Week 25 [7] | ||||||||
End point description |
Serum AP functional activity was measured by the Wieslab functional immunoassay method. Change from Baseline = Serum AP functional activity at Week 25 - Baseline Serum AP functional activity. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Serum AP functional activity.
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End point type |
Primary
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End point timeframe |
Baseline, Week 25
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| 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Free Hgb at Week 25 [8] | ||||||||
End point description |
Change from Baseline = free Hgb at Week 25 - Baseline free Hgb. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for free Hgb.
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End point type |
Primary
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End point timeframe |
Baseline, Week 25
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| Notes [8] - 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Grade 3 and Grade 4 Adverse Events (AEs), And AEs Leading To Discontinuation [9] | ||||||||||||||||
End point description |
An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the ‘Reported Adverse Events’ Section. Safety analysis set included all enrolled participants who received at least 1 dose of danicopan.
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End point type |
Primary
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End point timeframe |
Baseline up to 4.5 years
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| Notes [9] - 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: The statistical analysis was not planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in LDH Level at Weeks 49 and 169 | ||||||||||||
End point description |
Change from Baseline = Serum LDH levels at specified postbaseline visit - Baseline Serum LDH levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for LDH level. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 49 and 169
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Hgb Level in the Absence of RBC Transfusion at Weeks 49 and 169 | ||||||||||||
End point description |
Change from Baseline = Hgb levels at specified postbaseline visit - Baseline Hgb levels. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Hgb level. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 49 and 169
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Reticulocyte Counts at Weeks 49 and 169 | ||||||||||||
End point description |
Change from Baseline = reticulocyte count at specified postbaseline visit - Baseline reticulocyte count. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for reticulocyte count. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 49 and 169
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in PNH Clone Size at Weeks 49 and 73 | ||||||||||||
End point description |
The PNH clone size refers to the percentage of PNH-affected cells versus normal cells within the total cell population. Change from Baseline = PNH clone size at specified postbaseline visit - Baseline PNH clone size. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for PNH clone size. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 49 and 73
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in AP Complement Functional Activity at Weeks 49 and 145 | ||||||||||||
End point description |
Serum AP functional activity was measured by the Wieslab functional immunoassay method. Change from Baseline = Serum AP functional activity at specified postbaseline visit - Baseline Serum AP functional activity. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for Serum AP functional activity. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 49 and 145
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Free Hgb at Weeks 49 and 169 | ||||||||||||
End point description |
Change from Baseline = free Hgb at specified postbaseline visit - Baseline free Hgb. Baseline was the baseline value from the primary Study ACH471-100. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for free Hgb. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 49 and 169
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at Weeks 21, 41, and 153 | ||||||||||||||
End point description |
The FACIT-Fatigue scale is a collection of quality of life questionnaires pertaining to the management of fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days. Participants score each item on a 5-point scale: 0 (Not at all) to 4 (Very much). Total scores range from 0 to 52, with higher score indicating better quality of life. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for FACIT-Fatigue scale score. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 21, 41, and 153
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale (EORTC-QLQ-C30): Global Health Status/Qol Score at Weeks 21, 41, and 153 | ||||||||||||||
End point description |
EORTC-QLQ-C30 is comprised of 30 questions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) & other single items. For each item, high score = high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health (global health status) and quality of life, coded on 7-point scale (1=very poor to 7=excellent). Answers were converted into grading scale, with total score between 0 and 100. A high score represented a favourable outcome with a best quality of life for participant. Full analysis set included all enrolled and treated participants. Here, 'Overall number of participants analyzed' = participants with both baseline and the postbaseline assessments for EORTC-QLQ-C30 (Global Health Status/Qol) score. 'n' = participants evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 21, 41, and 153
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline up to 4.5 years
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Adverse event reporting additional description |
Safety analysis set included all enrolled participants who received at least 1 dose of danicopan.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Danicopan
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Reporting group description |
Participants in this study continued to receive danicopan tablets orally at the same dose (150, 175, or 200 mg TID) that they were receiving upon completion of the primary Study ACH471-100. Dose escalation was done in increments of 25 mg to a maximum of 250 mg TID, in case additional clinical benefit was expected as per Investigator and Sponsor decision. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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31 May 2017 |
• Enrollment was restricted to participants who completed Study ACH471-100 and demonstrated clinical benefit from danicopan.
• Study population was restricted to a maximum of 12 participants (from 30 participants).
• Danicopan trough concentration measurement for pharmacokinetics (PK) and ECG for safety assessments were added.
• Starting dose was increased to 150 mg TID and dose escalations up to 200 mg TID were permitted. A blood draw for LDH and liver function tests at 72 to 84 hours and the participants were required to have a clinic visit 2 weeks after dose escalation for safety evaluation and collection of samples for efficacy, pharmacodynamics (PD), and PK evaluation.
• 75 mg danicopan tablet was added to the list of supplied formulations.
• Dosing taper schedule corresponding to the newly updated permitted doses was added.
• Added a clarification that samples used for complement analyses will be stored from the beginning of this clinical study to 1 year after the clinical study report is published.
• Instructions for reporting SAEs or pregnancies were updated.
• Patient-reported outcomes (PRO) assessments (FACIT Fatigue and EORTC QLQ C30) were added. |
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22 Dec 2017 |
• Dose escalations of up to 250 mg TID in increments of 25 mg permitted.
• Dosing taper schedule corresponding to the newly updated permitted doses was added.
• Details of highly effective contraception requirements for both female and male participants including hormonal contraception, intrauterine device (IUD)/intrauterie system (IUS), bilateral tubal occlusion, abstinence, sterility requirements, vasectomy, condom use with female partner contraception (hormonal, IUD/IUS, bilateral tubal occlusion) were either added or updated.
• Requirement for urine pregnancy tests for females throughout the study as per the Schedule of Assessments, was added.
• Revised text to mention that participants who terminate early may be interviewed for PRO assessments based on local regulations or ethics committee (EC) requirements.
• Instructions for reporting SAEs were updated. |
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13 Mar 2018 |
• Inclusion criterion was updated for acceptable contraception (female) from date of informed consent to dosing Day 1 and highly effective contraception (male and female) from dosing Day 1 to 30 days (for females) and 90 days (for males) after the last dose of study intervention.
• Guidance on booster vaccinations against bacterial infections as per national and/or local guidelines or in their absence as per Advisory Committee on Immunization Practices (ACIP) guidelines was added.
• Female participants of childbearing potential were also required to have a negative serum pregnancy test during Screening and negative urine pregnancy test on Day 1.
• Instructions for participants discontinuing during the extension phase to have danicopan tapered and have follow-up visits were added. |
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04 Jun 2021 |
• Instructions for dose tapering were updated and 75 mg dose was removed from the dose tapering schedule as 75 mg tablets used in the study were no longer manufactured.
• PRO interviews were discontinued effective 30 Apr 2019.
• PK/PD samples were no longer required at the long-term extension clinic visits, taper visits, or follow-up visits.
• Instructions for reporting SAEs or pregnancies were updated due to a transition in the safety reporting process.
• To ensure patient safety and treatment continuity during the COVID-19 outbreak, physical visits were allowed to become telephone or videoconference visits, and safety laboratory tests were allowed using home healthcare laboratory sampling, local laboratories, or other appropriate clinical facilities.
• Language regarding COVID 19 risk assessment was added as per Medicines and Healthcare products Regulatory Agency (MHRA) requirements.
• Clarification regarding study requirements for participants from Study ACH471-103 to enroll into Study ACH228-110 and option to enter in another appropriate Alexion clinical study (if available), were added. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
