The effect of amantadine as add-on therapy for motor fluctuations in advanced Parkinson’s disease: a randomized double-blinded placebo-controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Toulouse

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

10 Oct 2025 → ongoing

Decision date (initial)

2024-08-30

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The main objective of this study is to evaluate the effect of amantadine as add-on therapy for the treatment of motor fluctuations (Off-time) in advanced Parkinson’s disease patients versus placebo after 3 months of treatment.

Secondary objectives 5

1. To evaluate the effect of amantadine as add-on therapy, versus placebo, in advanced PD patients, after three months of treatment: a) the rate of Off-time responders b) On the improvement of on-time without troublesome dyskinesia (“good-ON”); c) On the reduction of Off-related dystonia; d) On FoG, fatigue and global motor and non-motor functions; e) On QoL;
2. To assess the safety of amantadine in the study population
3. to determine if the polymorphism of Glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GRIN2B), and of the COMT, or of GBA and LRRK2 mutation carriers modify the effect of amantadine of off-times responses
4. to assess the feasibility of PDMonitor utilization in a subgroup of advanced PD patients
5. to evaluate the agreement among PDMonitor report changes and clinical scales.

Conditions and MedDRA coding

advanced Parkinson’s disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Parkinson’s disease diagnosis in agreement with the MDS criteria (Postuma et al., 2015) for at least 3 years
2. HY 2-3 in Med ON condition
3. Age: 30-80 years
4. Signs of motor fluctuations for at least 4 weeks before screening, with a mean total awake time in the off state of at least 2 h, including morning akinesia despite anti-parkinsonian drug adjustment (best medical treatment)”
5. Amantadine naïve (all other oral add-on treatments for motor fluctuations are allowed)Patients who have taken Amantadine less than 7 days can be included if they did not stop Amantadine because of side effects or lack of efficacy.
6. Patients affiliated or beneficiary of a social security scheme
7. Patients who signed the written informed consent form.
8. Patients in capacity to complete Hauser diaries
9. Concomitant anti-Parkinson drug use should be stable for at least 4 weeks prior to screening

Exclusion criteria 14

1. • Severe or unpredictable periods in the Off-state, or both
2. • Patients having any contraindication to amantadine treatment (see Summary of Product characteristic in the Appendix: known hypersensitivity to drugs of the amantadine class or any of the components, combination with anti-emetic neuroleptics, patient with a history of epilepsy, confusional state, hallucinations or severe psychoneurotic state not controlled by treatment, patient with a history of congestive heart failure or peripheral oedema, patients with history of mild eczema will be allowed to participate and closely monitored)
3. • A history of neuroleptic malignant syndrome or nontraumatic Rhabdomyolysis;
4. • renal failure and renal insufficiency (creatinine > 150 µmol/L)
5. • Has received any other investigational drug within 30 days or 5 half-lives (whichever is longer) prior to screening or plans to use an investigational drug (other than the study intervention) during the study
6. • states of agitation or confusion
7. • delirious syndromes or exogenous psychosis in the anamnesis
8. • Pregnant female subjects or potential childbearing female participant without highly effective contraception
9. • Clinically significant and unstable cardiovascular disease, psychiatric illness (including major depression, dementia, impulse control, disorders, and suicide ideation), or any other medical disorder that might have placed the patient at increased risk;
10. • Patient with behavioral disorder, ECMP item ≥ 3
11. • Patients with on-going advanced treatments: subcutaneous continuous apomorphine infusion, levodopa-carbidopa intestinal gel and foslevodopa/foscarbidopa subcutaneous pump;
12. • Patients with cognitive impairment (Mini Mental Status Examination < 26)
13. • Patients with a diagnosis of atypical parkinsonism (Progressive supranuclear Palsy, Multiple system atrophy, Lewy Body Dementia or Cortico-basal degeneration)
14. • Patients previously submitted to deep brain stimulation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The main evaluation criterion is the change from baseline to end-point (3 months) in motor fluctuation (Off-time) assessed by the Hauser diaries (average of 3 consecutive days).

Secondary endpoints 5

1. The change from baseline to end-point (3 months): a) Off-time responders rate ; b) The mean score of MDS-UPDRS part IV (Goetz et al., 2008b); c) The mean score of UDysRS part 2A (Goetz et al., 2008a) ; d) The mean score of New freezing of gait questionnaire (Nieuwboer et al., 2009); e) The mean score of Fatigue Severity Scale (Herlofson and Larsen, 2002; Krupp et al., 1989), MDS-UPDRS Part I-II-III (Goetz et al., 2007) f) The mean score of PDQ-39 (Jenkinson et al., 199
2. The safety of amantadine, expressed as: the percentage of AEs, of severe AEs, of serious AE and of patients’ discontinuation due to AEs, all over the three months of treatment.
3. The change from baseline to week 15 in motor fluctuation (Off-time) assessed by the Hauser diaries comparing patients with GRIN2B polymorphism vs. without, patients with COMTHH vs. patients with COMTLL and in mutated GBA/LRRK2 carriers vs. no GBA/LRRK2 mutation carriers;
4. The number of patients able to wear the PDMonitor during the first and the second week of assessment and the Short Assessment of Patient Satisfaction on PDMonitor in advanced PD patients;
5. the agreement in PD monitor outcomes changes from baseline to end-point (3 month) with clinical scales changes

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Toulouse

Sponsor organisation

Centre Hospitalier Universitaire De Toulouse

Address

2 Rue Viguerie

City

Toulouse

Postcode

31300

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Toulouse

Contact name

Dr Margherita Fabbri

Public contact point

Organisation

Centre Hospitalier Universitaire De Toulouse

Contact name

Amandine Pauze

Locations

1 EU/EEA country · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications