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NCT01896102

A Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

Completed Phase 2, PHASE3 Results posted Last updated 25 April 2022
What this trial tests

Phase 2, PHASE3 trial testing Lenti-D Drug Product (eli-cel) in Cerebral Adrenoleukodystrophy (CALD) in 32 participants. Completed in 26 March 2021.

Timeline
21 August 2013
Primary endpoint
26 March 2021
26 March 2021

Quick facts

Lead sponsorGenetix Biotherapeutics Inc.
PhasePhase 2, PHASE3
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment32
Start date21 August 2013
Primary completion26 March 2021
Estimated completion26 March 2021
Sites8 locations across France, United Kingdom, Germany, Argentina, Australia, United States

Drugs / interventions tested

Conditions studied

Sponsor

Genetix Biotherapeutics Inc. — full company profile →

Who can join

Under 17, male only, with Cerebral Adrenoleukodystrophy (CALD). 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.

Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 and Without Allo-HSCT or Rescue Cell Administration Primary · At Month 24

The 6 MFDs consisted of loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement. Month 24 MFD-Free survival criteria was defined as: alive at 24 months post-infusion; had not developed any of the MFDs by 24 months post-infusion; had not received rescue cell administration or allo-HSCT by 24 months post-infusion; and had not withdrawn from the study or had not been lost to follow-up by 24 months post-infusion. Percentage of participants who were alive and have none of the 6 major functional disabilities (MFDs) at Mo

GroupValue95% CI
Lenti-D Drug Product90.675.0 – 98.0
Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24 Primary · By Month 24

Acute GVHD graded on the Acute GVHD Grading Scale (I-IV): Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening; chronic GVHD was determined by the Investigator. Percentage of participants who experienced with either acute (\>= Grade II) or chronic GVHD at Month 24 were reported.

GroupValue95% CI
Lenti-D Drug Product0.00.0 – 10.9
Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24 Secondary · At Month 24

Percentage of participants who demonstrated resolution of gadolinium positivity (i.e., GdE-) on MRI at Month 24 were reported.

GroupValue95% CI
Lenti-D Drug Product86.769.3 – 96.2
Time to Sustained Resolution of Gadolinium Positivity on MRI Secondary · Up to Month 24

Sustained resolution of gadolinium positivity was defined as having at least two consecutive GdE- results by MRI without a subsequent evaluation indicating GdE+.

GroupValue95% CI
Lenti-D Drug Product7725 – 551
Number of Participants With Change in Total Neurologic Function Score (NFS) From Baseline up to Month 24 Secondary · Baseline up to Month 24

NFS was a 25-point score used to evaluate the severity of gross neurologic dysfunction in CALD by scoring 15 symptoms (functional domains) across 6 categories. Listed here are the 15 symptoms followed by their maximal score out of 25 points: a) Hearing / auditory processing problems-1, b) Aphasia/apraxia-1, c) Loss of communication-3, d) Vision impairment/field cut-1, e) Cortical blindness-2, f) Swallowing/other CNS dysfunctions-2, g) Tube feeding-2, h) Running difficulties/hyperreflexia-1, i) Walking difficulties/spasticity/spastic gait (no assistance)-1, j) Spastic gait (needs assistance)-2,

GroupValue95% CI
Lenti-D Drug Product4
Major Functional Disability (MFD)-Free Survival Rate Secondary · At 24 months after Lenti-D drug infusion

MFD-free survival rate was defined as percentage of participants from drug product infusion to either second transplant, MFD, or death due to any cause, whichever occurs first. MFD-free survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated MFD-free survival rate at 24 months after Lenti-D drug infusion was reported.

GroupValue95% CI
Lenti-D Drug Product90.673.7 – 96.9
Overall Survival Rate Secondary · At 24 months after Lenti-D drug infusion

Overall survival rate was defined as percentage of participants alive from date of Lenti-D drug product infusion (Day 0) to date of death of all causes. Overall survival rate was censored at the date of last visit if the participant were alive. Participants who are alive were censored at the date of last contact. Overall survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated overall survival rate at 24 months after Lenti-D drug infusion was reported.

GroupValue95% CI
Lenti-D Drug Product96.778.6 – 99.5
Proportion of Participants With Neutrophil Engraftment by 42 Days Post-drug Product Infusion Secondary · By 42 days post-drug infusion

Neutrophil engraftment (NE) was defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of \>= 0.5×10\^9 cells/Liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Percentage of participants with neutrophil engraftment by 42 Days post-drug product infusion were reported.

GroupValue95% CI
Lenti-D Drug Product100.089.1 – 100
Time to Neutrophil Engraftment Post-drug Product Infusion Secondary · By 42 days post-drug infusion

Neutrophil Engraftment was defined as achieving 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Time to neutrophil engraftment post-drug product infusion was reported.

GroupValue95% CI
Lenti-D Drug Product13.011 – 41
Proportion of Participants With Platelet Engraftment by Month 24 Secondary · By Month 24

Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of \>=20 × 10\^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts \>=20 × 10\^9 cells/L was the day of PE. Percentage of participants with Platelet Engraftment by Month 24 (Rel Day 730) were reported.

GroupValue95% CI
Lenti-D Drug Product10089.1 – 100.0
Time to Platelet Engraftment Post-drug Product Infusion Secondary · By Month 24

Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of \> or =20 × 10\^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts \>=20 × 10\^9 cells/L was the day of PE. Time to Platelet Engraftment post-drug product infusion up to Month 24 was reported.

GroupValue95% CI
Lenti-D Drug Product3216 – 60
Proportion of Participants With Engraftment Failure By Month 24 Secondary · By Month 24

Participants were considered to have primary engraftment failure if they did not achieve NE by Relative Day 43. A participant was considered to have secondary engraftment failure if they achieved and then subsequently lost NE by the Month 24, i.e., if they met both the conditions; Achieved NE by Relative Day 43 as defined above and had sustained decline in ANC to \< 0.5×10\^9 cells/L for 3 consecutive measurements on different days after Relative Day 43, without alternate etiology. First day of the 3 consecutive ANC decline to \< 0.5×10\^9 cells/L was considered the day of secondary engraftmen

GroupValue95% CI
Lenti-D Drug Product0.00.0 – 11.9

Adverse events — posted to ClinicalTrials.gov

Time frame: From date of informed consent up to Month 24. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Lenti-D Drug Product
Serious: 21/32 (66%)
Deaths: 1/32

Serious adverse events (25 terms)

ReactionSystemLenti-D Drug Product
Febrile neutropeniaBlood and lymphatic system disorders
PyrexiaGeneral disorders
Vascular device infectionInfections and infestations
Adrenal insufficiencyEndocrine disorders
Cardio-respiratory arrestCardiac disorders
Abdominal painGastrointestinal disorders
StomatitisGastrointestinal disorders
VomitingGastrointestinal disorders
Acute hepatic failureHepatobiliary disorders
Cystitis viralInfections and infestations
GastroenteritisInfections and infestations
InfluenzaInfections and infestations
Otitis mediaInfections and infestations
Viral infectionInfections and infestations
SinusitisInfections and infestations
Head injuryInjury, poisoning and procedural complications
Procedural PainInjury, poisoning and procedural complications
Spinal fractureInjury, poisoning and procedural complications
Decreased appetiteMetabolism and nutrition disorders
RhabdomyolysisMusculoskeletal and connective tissue disorders
DyskinesiaNervous system disorders
Neurological decompensationNervous system disorders
SeizureNervous system disorders
Acute kidney injuryRenal and urinary disorders
Respiratory distressRespiratory, thoracic and mediastinal disorders
Other adverse events (68 terms — click to expand)

ReactionSystemLenti-D Drug Product
ThrombocytopeniaBlood and lymphatic system disorders
AnaemiaBlood and lymphatic system disorders
NeutropeniaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
StomatitisGastrointestinal disorders
AlopeciaSkin and subcutaneous tissue disorders
Decreased appetiteMetabolism and nutrition disorders
Febrile neutropeniaBlood and lymphatic system disorders
HypokalaemiaMetabolism and nutrition disorders
Abdominal painGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
HeadacheNervous system disorders
LeukopeniaBlood and lymphatic system disorders
PyrexiaGeneral disorders
ConstipationGastrointestinal disorders
HypomagnesaemiaMetabolism and nutrition disorders
Catheter site painGeneral disorders
Alanine aminotransferase increasedInvestigations
Procedural PainInjury, poisoning and procedural complications
PruritusSkin and subcutaneous tissue disorders
LymphopeniaBlood and lymphatic system disorders
Aspartate aminotransferase increasedInvestigations
RashSkin and subcutaneous tissue disorders
HyphophosphataemiaMetabolism and nutrition disorders
Allergic transfusion reactionInjury, poisoning and procedural complications
Fluid RetentionMetabolism and nutrition disorders
Skin HyperpigmentationSkin and subcutaneous tissue disorders
HypertensionVascular disorders
Oral painGastrointestinal disorders
ProctitisGastrointestinal disorders
Vascular device infectionInfections and infestations
Rash Maculo papularSkin and subcutaneous tissue disorders
EnuresisPsychiatric disorders
BradycardiaCardiac disorders
TachycardiaCardiac disorders
Sinus bradycardiaCardiac disorders
ToothacheGastrointestinal disorders
Catheter site hemorrhageGeneral disorders
FatigueGeneral disorders

Most-reported serious reactions: Febrile neutropenia, Pyrexia, Vascular device infection, Adrenal insufficiency, Cardio-respiratory arrest, Abdominal pain, Stomatitis, Vomiting.

Data from ClinicalTrials.gov NCT01896102 adverse events section.

Sponsor's own description

This trial assessed the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector (also called elivaldogene autotemcel or eli-cel), for the treatment of cerebral adrenoleukodystrophy (CALD). A participant's blood stem cells were collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells were transplanted back into the participant following myeloablative conditioning. Participants in this study will be continuously followed in study LTF-304.

Publications & conference data

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

  1. Viral vector platforms within the gene therapy landscape.
    Bulcha JT, Wang Y, Ma H, Tai PWL, et al · · 2021 · cited 899× · PMID 33558455 · DOI 10.1038/s41392-021-00487-6
  2. Clinical use of lentiviral vectors.
    Milone MC, O'Doherty U. · · 2018 · cited 629× · PMID 29654266 · DOI 10.1038/s41375-018-0106-0
  3. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.
    Eichler F, Duncan C, Musolino PL, Orchard PJ, et al · · 2017 · cited 429× · PMID 28976817 · DOI 10.1056/nejmoa1700554
  4. Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders.
    Shahryari A, Saghaeian Jazi M, Mohammadi S, Razavi Nikoo H, et al · · 2019 · cited 168× · PMID 31608113 · DOI 10.3389/fgene.2019.00868
  5. A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders.
    Tucci F, Galimberti S, Naldini L, Valsecchi MG, et al · · 2022 · cited 109× · PMID 35288539 · DOI 10.1038/s41467-022-28762-2
  6. Cell therapies in the clinic.
    Wang LL, Janes ME, Kumbhojkar N, Kapate N, et al · · 2021 · cited 99× · PMID 34027097 · DOI 10.1002/btm2.10214
  7. Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1.
    Fridman V, Suriyanarayanan S, Novak P, David W, et al · · 2019 · cited 95× · PMID 30626650 · DOI 10.1212/wnl.0000000000006811
  8. Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.
    Duncan CN, Bledsoe JR, Grzywacz B, Beckman A, et al · · 2024 · cited 93× · PMID 39383458 · DOI 10.1056/nejmoa2405541

Verify or expand the search:

Other recruiting trials for Cerebral Adrenoleukodystrophy (CALD)

Currently open trials in the same condition.

Other Genetix Biotherapeutics Inc. trials

Trials by the same sponsor.

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing