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A Phase 1b, Prospective, Randomized, Double-blind, Placebo-controlled Trial Evaluating the Safety and Tolerability of Multiple Oral Doses of IRL757 in Participants with Parkinson’s Disease and Apathy

Trial ID
2025-523612-37-00
Protocol
IRL757C003
Sponsor
Integrative Research Laboratories Sweden AB

Trial statistics

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3
test molecules
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16
research sites
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4
countries
medical_information
1
disease
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19
investigators
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11
vendors

Diseases & Conditions

Parkinson's disease

Objectives

The primary objective of this trial is to evaluate the safety and tolerability of IRL757 following repeated daily dosing for 12 weeks in participants with Parkinson's disease who present moderate to severe symptoms of apathy. This assessment is clinically relevant as apathy represents a significant neuropsychiatric manifestation in Parkinson's disease that impacts patient functionality and quality of life, and establishing the safety profile of IRL757 is essential before evaluating its therapeutic potential in this population.

The secondary objective is to assess the change from baseline in apathy symptoms in participants with Parkinson's disease who have moderate to severe symptoms of apathy. This evaluation provides preliminary insight into the potential therapeutic effect of IRL757 on apathy severity in this patient population.

Participants

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of both **male** and **female** participants between **50 and 90 years of age** with diagnosed **Parkinson's disease** and **moderate to severe apathy**. Participants were required to have a **Hoehn and Yahr stage** of 4 or less and a **Montreal Cognitive Assessment (MoCA)** score of 20 or greater. Apathy was defined according to the International Society for CNS Clinical Trials and Methodology criteria, requiring persistent symptoms in at least two of three dimensions: diminished initiative, diminished interest, or diminished emotional expression/responsiveness, present for at least 4 weeks prior to screening. Participants were required to score at least −16 on the **Lille Apathy Rating Scale (LARS)** to confirm moderate to severe apathy. A primary caregiver spending more than 10 hours per week with the participant was required to accompany them to trial visits. Treatment with anti-Parkinson medications, **antidepressants**, and **cholinesterase inhibitors** was permitted if doses remained stable for 1 month before and throughout the trial.

Plans and Procedures

This clinical trial is designed as a **Phase 1b**, prospective, **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety and tolerability of multiple oral doses of **IRL757** in participants with **Parkinson's disease** and **apathy**. The trial investigates two dose levels of IRL757 (10 mg and 30 mg daily) administered as **capsules** via the **oral route**, compared against placebo capsules. The maximum treatment period is 84 days, with a maximum total dose of 2520 mg for both dose levels. The active substance IRL757 is of chemical origin. The study aims to assess the safety and tolerability of IRL757 after repeated daily dosing for 12 weeks in participants with Parkinson's disease who have moderate to severe symptoms of apathy.

Eligible participants include male and female individuals between 50 and 90 years of age with diagnosed Parkinson's disease according to the Movement Disorders Society Clinical Diagnostic Criteria. Participants must have a **Hoehn and Yahr stage** of 4 or less at screening and a **MoCA score** of 20 or greater at screening and baseline. Participants must meet the ISCTM definition of apathy, exhibiting at least one symptom in at least two of three dimensions (diminished initiative, diminished interest, or diminished emotional expression/responsiveness) that is persistent or frequently recurrent for at least 4 weeks prior to screening. Moderate to severe apathy is confirmed by a score of at least −16 on the **LARS** at screening and baseline. A primary caregiver who spends greater than 10 hours per week with the participant must be available to accompany the participant to trial visits. Treatment with anti-Parkinson drugs, antidepressants (with specified exceptions), and **cholinesterase inhibitors** is permitted if doses are stable for 1 month before randomization and remain stable during the trial.

The primary endpoints focus on safety and tolerability measures, including the frequency, seriousness, and severity of **adverse events**, changes from baseline in physical examinations, clinical laboratory tests, **vital signs**, **ECGs**, **C-SSRS**, the **QUIP-RS**, and daytime sleepiness assessed by the **ESS**. Secondary endpoints include changes from baseline in the **NPI-C** (apathy domain) and LARS. The estimated recruitment start date is November 17, 2025, with an estimated study end date of February 28, 2027.

Participants will undergo a screening visit to assess eligibility criteria, followed by a baseline visit where randomization occurs. The treatment period consists of repeated daily dosing for 12 weeks, during which participants will attend scheduled follow-up visits for safety assessments and efficacy evaluations. The end-of-study visit will occur after completion of the 12-week treatment period or upon early termination. The expected length of participant involvement is approximately 12 weeks for the treatment phase, plus additional time for screening and follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of adverse events, protocol violations, withdrawal of consent, or investigator discretion based on safety concerns.

Treatment

The experimental medication IRL757 is administered as a capsule formulation for oral use. The active substance in this investigational medicinal product is IRL757, which is of chemical origin. Two dose levels of IRL757 are evaluated in this clinical trial. The lower dose regimen consists of a maximum daily dose of 10 mg, while the higher dose regimen consists of a maximum daily dose of 30 mg. Both dose levels are administered via the oral route with repeated daily dosing over a treatment period of 84 days (12 weeks). The maximum total dose amount for both dosing regimens is 2520 mg over the entire treatment period.

Placebo capsules are utilized as the comparator treatment in this randomized, double-blind, placebo-controlled trial. The placebo is formulated as capsules to maintain blinding and ensure consistency with the active treatment administration. The placebo capsules are administered orally to match the route of administration of the experimental medication, thereby ensuring that participants and investigators remain blinded to treatment allocation throughout the study duration.

Efficacy

Efficacy will be assessed through secondary endpoints evaluating changes in apathy symptoms in participants with Parkinson's disease. The secondary endpoints include change from baseline in the Neuropsychiatric Inventory-Clinician rating scale (NPI-C) apathy domain and change from baseline in the Lille Apathy Rating Scale (LARS). These assessments will be conducted during the 12-week treatment period with repeated daily dosing of IRL757. At baseline, participants are required to have moderate to severe apathy based on a score of at least −16 on the LARS, and must meet the International Society for CNS Clinical Trials and Methodology (ISCTM) definition of apathy, demonstrating symptoms in at least two of three dimensions (diminished initiative, diminished interest, or diminished emotional expression/responsiveness) that are persistent or frequently recurrent for at least 4 weeks prior to screening. The primary caregiver, who spends greater than 10 hours per week with the participant, will accompany the participant to trial visits and participate in the assessments.

Inclusion and Exclusion Criteria

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Inclusion Criteria

  • Male and female participants between 50 and 90 years of age, inclusive, with diagnosed Parkinson’s disease according to the Movement Disorders Society Clinical Diagnostic Criteria for Parkinson's disease.
  • Hoehn and Yahr stage ≤ 4 at screening.
  • MoCA score of 20 or greater at screening and baseline.
  • Meets the ISCTM definition of apathy (criterion B), defined as exhibiting ≥ 1 symptom in ≥ 2 of the following 3 dimensions, that is persistent or frequently recurrent (ie, ≥ 3 days per week) for ≥ 4 weeks prior to screening: • Diminished initiative (less spontaneous and/or active than usual self; less likely to initiate usual activities such as hobbies, chores, self-care, conversation, work-related or social activities), • Diminished interest (less enthusiastic about usual activities, less interested in, or less curious about, events in their environment, less interested in activities and plans made by others, less interested in friends and family, less persistence in maintaining or completing tasks or activities), or • Diminished emotional expression/responsiveness (less spontaneous emotions, less affectionate compared to their usual self, expresses less emotion in response to positive or negative events, less concerned about the impact of their actions on other people, less empathy). The symptoms must represent a significant change from the participant’s usual behaviour and cause significant impairment in personal, social, or occupational functioning. Finally, the symptoms must not be due to psychiatric illness, intellectual disability, physical/motor disabilities, or changes in level of consciousness or the effects of substances.
  • Participants with moderate to severe apathy based on a score of at least −16 on the LARS at screening and baseline.
  • Availability of the primary caregiver, who spends greater than 10 hours a week with the participant and supervises his or her care, to accompany the participant to trial visits and to participate in the trial.
  • Treatment with anti-Parkinson drugs, antidepressants (except for those listed as prohibited medications in Section 6.6.1), and ChEIs is permitted if doses are stable for 1 month before randomization and remain stable during the trial.
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Exclusion Criteria

  • Any active, current psychiatric comorbidity (such as major depressive disorder, obsessive-compulsive disorder, etc) a) as assessed by the MINI at screening. b) as assessed by the MADRS at the baseline visit with a score > 18.
  • Score of > 2 in the MDS-UPDRS Part 1, Question 1.2 (hallucinations and psychosis).
  • Need for acute psychiatric hospitalization.
  • Participants who: a) Answer “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) within the last 6 months prior to screening or the baseline visit, OR b) Answer “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) within the last 6 months prior to screening or at the baseline visit, OR c) Answer “Yes” on any of the 5 C-SSRS Suicidal Behaviour Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behaviour) within 2 years prior to screening or at the baseline visit, OR d) In the opinion of the investigator, present a serious risk of suicide.
  • Subthalamic stimulation of less than 1 year from screening.
  • Subthalamic stimulation without stable parameters for 3 months from screening.
  • Clinically significant impulse control disorders (ICDs) as assessed by the QUIP-RS (score > 6).
  • Renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2 calculated based on cystatin C).
  • Moderately impaired hepatic function or advanced hepatic dysfunction as assessed by a Child-Pugh score B or C.
  • Significant communicative impairments that prohibit meaningful participation in the trial assessments.
  • Central nervous system abnormalities (eg, cerebral aneurysm) and/or other vascular abnormalities such as vasculitis or pre-existing stroke, motor tics, or family history or diagnosis of Tourette's syndrome, seizures (convulsions, epilepsy), or historical clinically significant abnormal electroencephalograms (EEGs).
  • History of cancer within 5 years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer, or in situ cervical cancer. The cancer must not be active or currently under treatment except for potentially long-term stable medications.
  • Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
  • Any planned major surgery within the duration of the trial.
  • Any positive result at screening for serum hepatitis B surface antigen, hepatitis C antibody, or HIV.
  • Any vital signs values outside of the following ranges after 10 minutes of supine rest at the time of screening: a) Systolic blood pressure (SBP) > 150 mmHg b) Diastolic blood pressure (DBP) > 90 mmHg c) Heart rate < 50 or > 100 beats per minute.
  • Participants with a history of hypertension must have stable blood pressure for the 3 months prior to the trial, defined as blood pressure < 150/90 mmHg. If this criterion is not met the participant is not eligible for the trial.
  • Prolonged QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec for male participants or > 470 msec for female participants, cardiac arrhythmias, or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the investigator.
  • History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to IRL757.
  • Current nicotine use; irregular nicotine use less than 3 times per week is allowed before the screening visit.
  • Positive screen for illicit drugs (including cannabinoids) and/or abuse or positive screen for alcohol at screening or on Day 1 prior to administration of the IMP.
  • Use of anabolic steroids.
  • Use of antipsychotics.
  • The participant is unwilling or unable to discontinue taking alpha-2 adrenergic receptor antagonists and/or cytochrome P450 (CYP) inhibitor or substrate drugs at least 14 days or 5 times the half-life of the drug (whichever is longer) before randomization (see Table 6.6.1-1).
  • Excessive or variable daily caffeine consumption (ie, exceeding 3 cups per day) for the 2 weeks prior to screening.
  • Plasma donation within 1 month of screening or any blood donation/blood loss > 450 mL during the 3 months prior to screening
  • Participants who are breastfeeding.
  • Participants who have a positive pregnancy test result prior to receiving IMP.
  • Heterosexually active participants of reproductive potential (PORP) / POCBP who do not agree to use a highly effective method of birth control or remain fully abstinent from sexual activity with the potential for conception, per the guidelines in Section 10.3. Female participants of nonchildbearing potential (permanently sterilized [ie, hysterectomy, bilateral oophorectomy], postmenopausal for at least 12 months, or otherwise incapable of pregnancy) and male participants who have had a bilateral orchiectomy are eligible for enrolment
  • Participants who do not agree to refrain from donating sperm or eggs from trial screening through 90 days (for sperm) and 30 days (for eggs) after the last dose of IMP.
  • Participants who have participated in a clinical trial involving an investigational drug or device within the last 90 days or who participated in more than 2 clinical trials involving an investigational drug or device within the past year.
  • The investigator considers the participant unlikely to comply with trial procedures, restrictions, and requirements.
  • Any condition that, in the opinion of the investigator, makes it medically inappropriate or risky for the participant to enrol in the trial.

Trial Status by Country

Country Status Start of Recruitment Planned Patients
Bulgaria BulgariaRecruiting17 Nov 202535
Germany GermanyRecruiting17 Nov 202520
Poland PolandRecruiting17 Nov 202535
Spain SpainRecruiting17 Nov 202535

Sites & Investigators

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name Role in Trial Formulation Administration Max Daily Dose Treatment Duration EU MP Number
Placebo capsules
PlaceboN/A———N/A
IRL757
TestCAPSULEORAL1084PRD12759826
IRL757
TestCAPSULEORAL3084PRD12759827

Conditions Studied in This Trial