NCT02908685: SUNFISH

A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants

Completed Phase 2 Results posted Last updated 24 April 2024

What this trial tests

Phase 2 trial testing Placebo in Muscular Atrophy, Spinal in 231 participants. Completed in 2 October 2023.

Timeline

19 October 2016

Primary endpoint
6 September 2019

2 October 2023

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	sequential
Masking	double
Primary purpose	treatment
Enrollment	231
Start date	19 October 2016
Primary completion	6 September 2019
Estimated completion	2 October 2023
Sites	45 locations across France, Italy, Japan, Russia, Belgium, Serbia, United Kingdom, Germany

Drugs / interventions tested

• Placebo
• Risdiplam (RISDIPLAM) — full drug profile →

Conditions studied

• Muscular Atrophy, Spinal — all drugs for Muscular Atrophy, Spinal →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Adults 2 to 25, any sex, with Muscular Atrophy, Spinal. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg Primary · Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)

The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in

Group	Value	95% CI
Part 1: All Risdiplam	5

Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg Primary · Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)

The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in

Group	Value	95% CI
Part 1: All Risdiplam	0.25

Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 Primary · Baseline (Day-1) and Month 12

The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Hig

Group	Value	95% CI
Part 2: Risdiplam	1.36	0.61 – 2.11
Part 2: Placebo	-0.19	-1.22 – 0.84

Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 Secondary · At Month 12

The MFM32 comprises 32 items that evaluate physical function. The scoring of each task uses a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. A change in MFM32 total score of threshold \>/=3 represents marked improvement in this measure. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants d

Group	Value	95% CI
Part 2: Risdiplam	38.3	28.94 – 47.58
Part 2: Placebo	23.7	12.03 – 35.43

Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 Secondary · Baseline (Day-1) and Month 12

The RULM is a 20 items scale that assesses the proximal and distal motor functions of the arm. There is an entry item and the remaining 18 items are scored on the 3 point scale of: 0: cannot complete task independently; 1: modified method but can complete task independently; 2: completes task without any assistance, and with 1 item scored on a 2 point scale of as a can/cannot score with 1 as the highest score. The RULM total score is the sum of 19 items scores with range of 0-37, and the entry item does not contribute to the total score. Higher scores indicate greater upper limb function. A po

Group	Value	95% CI
Part 2: Risdiplam	1.61	1.00 – 2.22
Part 2: Placebo	0.02	-0.83 – 0.87

Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 Secondary · Baseline (Day-1) and Month 12

The HFMSE scale contains 33 items, which are scored on a 3-point Likert-type scale (0-2) and summed to derive the total score, with lower scores indicating greater impairment. The HFMSE contains a series of assessments designed to assess important functional abilities, including standing, transfers, ambulation, and proximal and axial function. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate greater motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy h

Group	Value	95% CI
Part 2: Risdiplam	0.95	0.29 – 1.61
Part 2: Placebo	0.37	-0.54 – 1.28

Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years Secondary · Baseline (Day-1) and Month 12

Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced vital capacity (FVC) is the total volume that can be exhaled after inhaling maximally. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment unt

Group	Value	95% CI
Part 2: Risdiplam	-5.16	-7.93 – -2.39
Part 2: Placebo	-3.11	-6.59 – 0.74

Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 Secondary · Baseline (Day-1) and Month 12

The SMA Independence Scale (SMAIS) was developed specifically for SMA participants in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants

Group	Value	95% CI
Part 2: Risdiplam	1.65	0.66 – 2.63
Part 2: Placebo	-0.91	-2.23 – 0.42

Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 Secondary · At Month 12

The Clinical Global Impression of Change (CGI-C) is used to score a clinician's impression of a participant's change in global health. The CGI-C is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "improved" included responses of "very much improved, "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data as

Group	Value	95% CI
Part 2: Risdiplam	47.5	38.15 – 56.86
Part 2: Placebo	40.0	26.77 – 53.23

Part 2: Percentage of Participants Who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12 Secondary · At Month 12

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. Logistic regression analysis was performed b

Group	Value	95% CI
Part 2: Risdiplam	69.6	60.72 – 78.41
Part 2: Placebo	54.2	40.68 – 67.80

Part 2: Percentage of Participants Who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12 Secondary · At Month 12

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0-cannot initiate the task or maintain the starting position; 1-performs the task partially; 2-performs the task incompletely or imperfectly; 3-performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the total score. Higher scores indicate increased motor function. Standard error of measurement (SEM) is derived using 32 items scores and total

Group	Value	95% CI
Part 2: Risdiplam	28.7	20.65 – 37.88
Part 2: Placebo	16.9	8.44 – 28.97

Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 Secondary · Baseline (Day-1) and Month 12

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1 items score are summed and expressed on 0-100 scale for the MFM D1 total score. Higher scores indicate increased motor function. A positive change from Baseline indicate

Group	Value	95% CI
Part 2: Risdiplam	0.37	-0.12 – 0.87
Part 2: Placebo	-0.26	-0.94 – 0.42

Adverse events — posted to ClinicalTrials.gov

Time frame: Part 1 and Part 2: Up to approximately 5 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1 Group A: Adolescents and Adults (3 mg Risdiplam)

Serious: 1/10 (10%)

Deaths: 0/10

Part 1 Group A: Adolescents and Adults (5 mg Risdiplam)

Serious: 0/10 (0%)

Deaths: 0/10

Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled)

Serious: 0/6 (0%)

Deaths: 0/6

Part 1 Group B: Children (0.02 mg/kg Risdiplam)

Serious: 0/7 (0%)

Deaths: 0/7

Part 1 Group B: Children (0.05 mg/kg Risdiplam)

Serious: 0/14 (0%)

Deaths: 0/14

Part 1 Group B: Children (0.15 mg/kg Risdiplam)

Serious: 0/21 (0%)

Deaths: 0/21

Part 1 Group B: Children (0.25 mg/kg Risdiplam)

Serious: 0/7 (0%)

Deaths: 0/7

Part 1 Group B: Children (Placebo-Control Period Pooled)

Serious: 1/10 (10%)

Deaths: 0/10

Part 1 Group A: OLE

Serious: 5/20 (25%)

Deaths: 0/20

Part 1 Group B: OLE

Serious: 9/31 (29%)

Deaths: 0/31

Part 2 Placebo-Controlled: Risdiplam

Serious: 24/120 (20%)

Deaths: 0/120

Part 2 Placebo-Controlled: Placebo

Serious: 11/60 (18%)

Deaths: 0/60

Part 2 OLT: Risdiplam/Risdiplam

Serious: 25/117 (21%)

Deaths: 0/117

Part 2 OLT: Placebo/Risdiplam

Serious: 4/59 (7%)

Deaths: 0/59

Part 2 OLE: Risdiplam

Serious: 34/175 (19%)

Deaths: 1/175

Serious adverse events (89 terms)

Reaction	System	Part 1 Group A: Adolescent…	Part 1 Group A: Adolescent…	Part 1 Group A: Adolescent…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group A: OLE	Part 1 Group B: OLE	Part 2 Placebo-Controlled:…	Part 2 Placebo-Controlled:…	Part 2 OLT: Risdiplam/Risd…	Part 2 OLT: Placebo/Risdip…	Part 2 OLE: Risdiplam
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Gastritis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Bacteraemia	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Lower respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Oesophagitis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Appendicitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pneumonia mycoplasmal	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Concussion	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Near drowning	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Chronic respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Spontaneous haematoma	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Cryptorchism	Congenital, familial and genetic disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—

Other adverse events (125 terms — click to expand)

Reaction	System	Part 1 Group A: Adolescent…	Part 1 Group A: Adolescent…	Part 1 Group A: Adolescent…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group B: Children (…	Part 1 Group A: OLE	Part 1 Group B: OLE	Part 2 Placebo-Controlled:…	Part 2 Placebo-Controlled:…	Part 2 OLT: Risdiplam/Risd…	Part 2 OLT: Placebo/Risdip…	Part 2 OLE: Risdiplam
COVID-19	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pharyngitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Rhinitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Influenza like illness	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Ear pain	Ear and labyrinth disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Tonsillitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Acne	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Eczema	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Hypersensitivity	Immune system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Conjunctivitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Gastroenteritis viral	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Viral infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—

Most-reported serious reactions: Pneumonia, Femur fracture, Gastroenteritis, Influenza, Upper respiratory tract infection, Gastritis, Pyrexia, Bacteraemia.

Data from ClinicalTrials.gov NCT02908685 adverse events section.

Sponsor's own description

Multi-center, randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of Risdiplam in adult and pediatric participants with Type 2 and Type 3 SMA. The study consists of two parts, an exploratory dose finding part (Part 1) of Risdiplam for 12 weeks and a confirmatory part (Part 2) of Risdiplam for 24 months.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Phenotypic drug discovery: recent successes, lessons learned and new directions.
   Vincent F, Nueda A, Lee J, Schenone M, et al · · 2022 · cited 204× · PMID 35637317 · DOI 10.1038/s41573-022-00472-w
2. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial.
   Mercuri E, Deconinck N, Mazzone ES, Nascimento A, et al · · 2022 · cited 154× · PMID 34942136 · DOI 10.1016/s1474-4422(21)00367-7
3. Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives.
   Dangouloff T, Servais L. · · 2019 · cited 149× · PMID 31632042 · DOI 10.2147/tcrm.s172291
4. Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study.
   Chabanon A, Seferian AM, Daron A, Péréon Y, et al · · 2018 · cited 122× · PMID 30048507 · DOI 10.1371/journal.pone.0201004
5. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.
   Poirier A, Weetall M, Heinig K, Bucheli F, et al · · 2018 · cited 111× · PMID 30519476 · DOI 10.1002/prp2.447
6. Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine.
   Chaytow H, Faller KME, Huang YT, Gillingwater TH. · · 2021 · cited 103× · PMID 34337562 · DOI 10.1016/j.xcrm.2021.100346
7. New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges.
   Messina S, Sframeli M. · · 2020 · cited 86× · PMID 32668756 · DOI 10.3390/jcm9072222
8. Treating pediatric neuromuscular disorders: The future is now.
   Dowling JJ, D Gonorazky H, Cohn RD, Campbell C. · · 2018 · cited 83× · PMID 28889642 · DOI 10.1002/ajmg.a.38418