Clinical Trial Results:
A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and Safety of a 6-Week Treatment Regimen of ALK4290 in Patients with Newly Diagnosed Wet Age-Related Macular Degeneration (wAMD).
|
Summary
|
|
EudraCT number |
2017-004227-75 |
Trial protocol |
HU PL |
Global end of trial date |
18 Nov 2018
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
24 Dec 2021
|
First version publication date |
24 Dec 2021
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
ALK4290-201
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT03558061 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Alkahest, Inc.
|
||
Sponsor organisation address |
125 Shoreway Road, Suite D, San Carlos, United States, CA 94070
|
||
Public contact |
Head of Communications, Alkahest, Inc., 001 650-801-0474,
|
||
Scientific contact |
Head of Communications, Alkahest, Inc., 001 650-801-0474,
|
||
|
Paediatric regulatory details
|
|||
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
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
31 Jan 2020
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
18 Nov 2018
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
18 Nov 2018
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective of this study was to investigate the therapeutic effects of a 6-week, twice daily oral dosing regimen of ALK4290 on best corrected visual acuity (BCVA) in newly diagnosed subjects with wAMD who were treatment-naïve (i.e., no previous treatment in the study eye).
|
||
Protection of trial subjects |
This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with International Conference on Harmonization Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those providing greater protection to the safety of study participants.
Subject Information and Consent
Written informed consent was obtained prior to the subject entering the study (before initiation of protocol-specific procedures). The investigators explained the nature, purpose, and risks of the study to each subject. Each subject was informed that he/she could withdraw from the study at any time and for any reason. Each subject was given sufficient time to consider the implications of the study before deciding whether to participate. Each informed consent was appropriately signed and dated by the subject and/or their legally authorized representative and the person obtaining consent (Appendix 16.1.3). A copy of the signed consent form was provided to the subject and/or their legally authorized representative. By signing the informed consent form, all parties agreed they will complete the evaluations required by the study, unless they withdrew voluntarily or were terminated from the study for any reason.
|
||
Background therapy |
ALK4290 was self-administered orally twice daily for a total daily dose of 800 mg from Visit 2 (Day 1) to Visit 8 (Day 43 ±1). At each study visit, all ophthalmic examinations and safety assessments were performed before administration of ALK4290. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Apr 2018
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Poland: 22
|
||
Country: Number of subjects enrolled |
Hungary: 8
|
||
Worldwide total number of subjects |
30
|
||
EEA total number of subjects |
30
|
||
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) |
4
|
||
From 65 to 84 years |
24
|
||
85 years and over |
2
|
||
|
|||||||
|
Recruitment
|
|||||||
Recruitment details |
The subject participation period, inclusive of Screening, was approximately 11 weeks (up to 1 week for Screening, a 6-week treatment period, and 4 weeks of follow-up), unless prematurely discontinued. All subjects underwent a Screening visit, Baseline/Treatment visit(s), End of Treatment (EOT) visit, and Follow-up visits. | ||||||
|
Pre-assignment
|
|||||||
Screening details |
Men and women with newly diagnosed active CNV secondary to AMD, diagnosed by a retinal specialist that met ophthalmic inclusion criteria applied to the study eye: | ||||||
|
Period 1
|
|||||||
Period 1 title |
baseline (overall period)
|
||||||
Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
|
||||||
Blinding used |
Not blinded | ||||||
|
Arms
|
|||||||
|
Arm title
|
baseline | ||||||
Arm description |
ALK4290 was self-administered orally twice daily for a total daily dose of 800 mg from Visit 2 (Day 1) to Visit 8 (Day 43 ±1). | ||||||
Arm type |
active treatment | ||||||
Investigational medicinal product name |
ALK4290
|
||||||
Investigational medicinal product code |
ALK4290
|
||||||
Other name |
|||||||
Pharmaceutical forms |
Coated tablet
|
||||||
Routes of administration |
Gastroenteral use
|
||||||
Dosage and administration details |
ALK4290 was self-administered orally twice daily for a total daily dose of 800 mg from Visit 2 (Day 1) to Visit 8 (Day 43 ±1).
|
||||||
|
|||||||
| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One patient has resigned and was not included in the beseline group |
|||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
baseline
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects with BCVA between 24 and 70 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Subject analysis sets
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
• Primary Efficacy Analysis
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The primary endpoint was the mean change from baseline (V 2/Day 1) to EOT (V 8/Day 43) in BCVA letter score of the study eye as measured by the ETDRS testing method using the Evaluable set. BCVA was measured at the beginning of every study visit and change from Baseline for each subject was calculated as Study visit minus Baseline visit. Quantitative summary statistics were used to summarize the BCVA letter score and change from Baseline at each visit. A two-tailed, one-sample t-test was used to assess the mean change from Baseline in BVCA letter score at each visit, in which the change from baseline BCVA letter score was compared to a reference value of 0 .Additionally, the number of subjects with change from Baseline in BCVA letter score for the following categories summarized with counts and percentages:
• ≥15 letters
• <15 and ≥10 letters
• <10 and ≥5 letters
• <5 and 0 letters
• <0 and >-5 letters
• ≤- 5 and >-10 letters
• ≤-10 and >-15 letters
• ≤-15 letters
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
baseline
|
||
Reporting group description |
ALK4290 was self-administered orally twice daily for a total daily dose of 800 mg from Visit 2 (Day 1) to Visit 8 (Day 43 ±1). | ||
Subject analysis set title |
• Primary Efficacy Analysis
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The primary endpoint was the mean change from baseline (V 2/Day 1) to EOT (V 8/Day 43) in BCVA letter score of the study eye as measured by the ETDRS testing method using the Evaluable set. BCVA was measured at the beginning of every study visit and change from Baseline for each subject was calculated as Study visit minus Baseline visit. Quantitative summary statistics were used to summarize the BCVA letter score and change from Baseline at each visit. A two-tailed, one-sample t-test was used to assess the mean change from Baseline in BVCA letter score at each visit, in which the change from baseline BCVA letter score was compared to a reference value of 0 .Additionally, the number of subjects with change from Baseline in BCVA letter score for the following categories summarized with counts and percentages:
• ≥15 letters
• <15 and ≥10 letters
• <10 and ≥5 letters
• <5 and 0 letters
• <0 and >-5 letters
• ≤- 5 and >-10 letters
• ≤-10 and >-15 letters
• ≤-15 letters
|
||
|
||||||||||
End point title |
Baseline mean BCVA | |||||||||
End point description |
The primary efficacy analysis was evaluated at a two-sided significance level of 0.20. The mean (SD) BCVA score at Baseline was 56.8 (10.22) letters and at EOT was 63.7 (16.42) letters. The mean (SD) BCVA score improved by 7.0 (12.51) (95% confidence interval [CI] 2.2, 11.7; p=0.0056) from Baseline to EOT. The least square mean was 7.8 (95% CI 2.3, 13.2; p=0.0065).
Mean changes in BCVA from Baseline to EOT were as follows: ≥0 letters gained in 24 (82.8%) subjects; ≥15 letters gained in 6 (20.7%) subjects; <15 and ≥10 letters gained in 6 (20.7%) subjects; <10 and ≥5 letters gained in 4 (13.8%) subjects; and <5 and ≥0 letters gained in 8 (27.6%) subjects. Five (17.2%) subjects lost BCVA letters.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
mean change from baseline (Visit 2/Day 1) to EOT (Visit 8/Day 43) in BCVA letter score of the study eye as measured by the ETDRS
|
|||||||||
|
||||||||||
Attachments |
Categorical Summary of Study Eye BCVA Letter Score |
|||||||||
Statistical analysis title |
mean change in BCVA letter score | |||||||||
Comparison groups |
baseline v • Primary Efficacy Analysis
|
|||||||||
Number of subjects included in analysis |
58
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
other [1] | |||||||||
P-value |
≥ 0.05 [2] | |||||||||
Method |
t-test, 2-sided | |||||||||
Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
0.2
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0 | |||||||||
upper limit |
100 | |||||||||
Variability estimate |
Standard deviation
|
|||||||||
Dispersion value |
7
|
|||||||||
| Notes [1] - The presentation of baseline characteristics was based on the Intent-to-Treat (ITT) dataset. A mixed model accounting for repeated measures was used to analyze BCVA. This model included the change from Baseline in BCVA letter score as the response variable and Baseline BCVA letter score, smoking status, and visit as explanatory variables for adjustment. Least squares (LS) means for each visit was calculated along with corresponding 95% CIs and p-values. [2] - The mean (SD) BCVA score improved by 7.0 (12.51) (95% confidence interval [CI] 2.2, 11.7; p=0.0056) from Baseline to EOT. The least square mean was 7.8 (95% CI 2.3, 13.2; p=0.0065). |
||||||||||
|
||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All AEs, serious and non-serious, occurring during the course of the clinical trial (i.e., from signing the informed consent through the Follow-up period) were collected, documented, and reported to the sponsor by the investigator on the appropriate eCRF
|
|||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
An AE occurring during the treatment period was based on changes in the patient’s physical examination, test results, and/or signs and symptoms. The severity of each AE was summarized according to the CTCAE version 4.03. Adverse Events were coded using the MedDRA, v. 21.
|
|||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||
Dictionary version |
21.0
|
|||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||
Reporting group title |
treatment-emergent AE (TEAEs)
|
|||||||||||||||||||||||||||||||||
Reporting group description |
The most frequently reported non-ocular TEAEs occurred in the SOCs of musculoskeletal and connective tissue disorders (8 [26.7%] subjects), followed by infections and infestations (4 [13.3%] subjects), and general disorders and administration site conditions and investigations (3 [10.0%] subjects each). The most frequent non-ocular TEAE by PT was arthralgia (5 [16.7%] subjects), back pain (3 [10.0%] subjects), and cystitis and headache (2 [6.7%] subjects each). | |||||||||||||||||||||||||||||||||
Reporting group title |
ALK4290-related (includes definitely and possibly related) AE
|
|||||||||||||||||||||||||||||||||
Reporting group description |
The most frequently reported related non-ocular TEAEs occurred in the SOCs of musculoskeletal and connective tissue disorders (5 [16.7%] subjects), followed by general disorders and administration site conditions (3 [10.0%] subjects), and investigations and nervous system disorders (2 [6.7%] subjects each). The most frequent related non-ocular TEAEs by PT were arthralgia (4 [13.3%] subjects) and headache (2 [6.7%] subjects). | |||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
19 Mar 2018 |
The Protocol Version 2.0 (Amendment 1) dated 19 March 2018 replaced Protocol Version 1.0 dated 27 October 2017.
Revised inclusion criteria, as requested by the Polish Department of Clinical Trials for Medicinal Products, added the following sentence to bullet 5: “Women of childbearing potential must have a negative serum pregnancy test at Screening/Visit 1, the first treatment visit, and the last treatment visit. Women of childbearing potential and men must agree to use highly effective contraception (Clinical Trial Facilitation Group 2014) prior to study entry. A woman was considered of childbearing potential following menarche and until becoming postmenopausal (no menses for at least 2 years without an alternative cause).”
Revised number of categories of relatedness of AE in the previous version incorrectly stated there were four categories of relatedness which was revised to state there are three categories of relatedness.
Per request from the Polish Department of Clinical Trials for Medicinal Products, added the “serum pregnancy test (in women of childbearing potential)” to Visit 1, Visit 2, Visit 8; and added pregnancy test at Screening/Visit 1 (as applicable per Inclusion Criteria), first treatment visit, and final treatment visit.
Added reference to define “highly effective” contraception as per the Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy testing in clinical trials.
Throughout the protocol, where appropriate, updated terminology of “patient” to “subject” for clarity and standardization, as a “patient” becomes a “subject” following study enrollment.
|
||
15 May 2018 |
The Protocol Version 3.0 (Amendment 2.0) dated 15 May 2018 replaced Protocol Version 1.0 dated 27 October 2017 (for Hungary) and Protocol Version 2.0 (Amendment 1) dated 19 March 2018 (for Poland). In Version 3.0, the two former country-specific protocols were combined into a single protocol for global standardization and compliance. Unless otherwise specified, the following changes were applicable for both Hungary and Poland.
The exploratory endpoint of CRT was changed to CST. Similar change made in inclusion criteria in bullet 1/sub-bullet 2.
Due to staffing assignment changes within Alkahest, the Authorized Representative (Signatory) / Responsible Party has been changed. The email address has also been updated to reflect this change.
Inclusion Criteria in bullet 5 was revised to include requirements related to pregnancy and pregnancy testing for Hungary and Poland. The requirements have not changed in either country from V1.0/V2.0 to V3.0 other than being combined to create a single protocol.
Per request from the Polish Department of Clinical Trials for Medicinal Products, added the “serum pregnancy test (in women of childbearing potential)” to Visit 1, Visit 2, Visit 8 in Visit Procedures; and added pregnancy test at Screening/Visit 1 (as applicable per Inclusion Criteria), first treatment visit, and final treatment visit in Schedule of events (amendment to Hungary protocol). Added the word- for Poland only in all these changes (amendment to both Poland and Hungary protocol). |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
