Evicenter
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Juvmo (tavapadon)

Parkinson's disease

Also known as CVL-751
Manufacturer
AbbVie
Regulatory submission
NDA submitted September 2025
Last updated
217 sources

Clinical evidence

NCT02847650

35 evidence topics · 3 sources

Objective
Trial objective: flexible-dose PF-06649751 in early Parkinson's disease

“The purpose of this study is to evaluate the efficacy, safety and tolerability of PF-06649751 in Parkinson's disease patients at early stage of the disease.” (opens the source at this quote in a new tab)

Objective as stated in the publication

“A 15-week, phase II, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy and safety of flexible-dose PF-06649751 in subjects with early stage Parkinson’s disease (ClinicalTrials.gov identifier: NCT02847650).” (opens the source at this quote in a new tab)

Location and study date
Summary: sponsor, identifiers, and registry status

The registry record for NCT02847650 gives Pfizer as sponsor and B7601011 as the sponsor study number. The actual study start date was 17 October 2016 and the actual study completion date was 29 January 2018. The overall status is terminated, with 57 participants enrolled, and results have been posted.

Study period, sites, and countries

“This phase II, double-blind, randomized, placebo-controlled, flexible-dose, 15-week study in subjects with early stage Parkinson’s disease was conducted from October 2016 (first subject first visit) to January 2018 (last subject last visit) at 23 sites in the United States, France, Germany, and Israel (ClinicalTrials.gov identifier: NCT02847650).” (opens the source at this quote in a new tab)

Study design
Screening, dose optimization, maintenance, and follow-up periods

“The study consisted of a 30-day screening period, a 15-week double-blind treatment period (9 week dose optimization and 6 week dose maintenance), and a 28-day follow-up period.” (opens the source at this quote in a new tab)

Randomization and stratification

“At Visit 1, subjects were stratified by region and randomized (1:1) in a double-blind manner to either oral (tablet) PF-06649751 or matching placebo.” (opens the source at this quote in a new tab)

Eligibility criteria
Inclusion criteria

“Study inclusion criteria were as follows: males agreeing to use contraception or females of nonchildbearing potential; aged 45–80; a clinical diagnosis of Parkinson’s disease (Hoehn & Yahr Stage I–III); an MDS-UPDRS Part III score ⩾10; treatment naïve or history of prior incidental treatment with dopaminergic agents for no more than 28 days and not within at least 7 days prior to randomization; a Mini-Mental State Examination (MMSE) score ⩾26; body mass index (BMI) of 17.5–35 kg/m2; and a total body weight ⩾45 kg.” (opens the source at this quote in a new tab)

Exclusion criteria

“Key exclusion criteria included: history or clinical features consistent with an atypical Parkinsonian syndrome (e.g. progressive supranuclear palsy, multiple system atrophy, and cortico basal degeneration); significant psychiatric disease (except minor or treated stable depression); risk of suicide; current malignancy (except nonmetastatic basal or squamous cell carcinoma of the skin); significant cardiovascular disease; cognitive impairment that would interfere with ability to comply with study procedures; pregnancy; currently breastfeeding; male subjects with pregnant partner; 12 lead electrocardiogram (ECG) demonstrating a QTcF interval >450 ms (>470 ms for females) or a QRS interval >120 ms.” (opens the source at this quote in a new tab)

Permitted and prohibited concomitant medications

“MAO B inhibitors, amantadine, and anticholinergic drugs were permitted if subjects were on stable doses of these anti-parkinsonian medications for at least 42 days prior to Visit 1.” (opens the source at this quote in a new tab)

“Prior treatment with levodopa or dopamine receptor agonists for more than 28 days, or any treatment with these agents within 7 days of Visit 1, was prohibited. Rescue anti-parkinsonian medication use after first dose of study treatment was not permitted.” (opens the source at this quote in a new tab)

Treatment
Titration schedule and dose adjustment

“Subjects administered medication once-daily (morning) and recorded administration in a dosing diary.” (opens the source at this quote in a new tab)

“The recommended dosing schedule was as follows: 0.25 mg (days 1–7), 0.75 mg (days 8–14), 1.5 mg (days 15–21), 3 mg (days 22–28), 5 mg (days 29–35), 7 mg (days 36–42), 11 mg (days 43–49), and 15 mg (from day 50 onward). A dose increase from 0.25 mg to 0.75 mg was mandatory at Visit 2, and subjects who could not tolerate 0.25 mg were discontinued. Dosing decisions (increase/decrease/stay at current dose) were made on a weekly basis thereafter, up to Visit 10, based on investigator assessment of an individual subject achieving an optimal balance of motor symptom control and tolerability. Dosing adjustments after week 10 required consultation with the sponsor’s study clinician. The minimum recommended dose level was 3 mg.” (opens the source at this quote in a new tab)

Maintenance doses achieved

“The maintenance dose (defined as the dose received for at least the last 4 weeks of the maintenance phase) for subjects in the PF-06649751 group was as follows: 0.75 mg (n = 1), 1.5 mg (n = 1), 3 mg (n = 5), 5 mg (n = 1), 7 mg (n = 2), 11 mg (n = 4), and 15 mg (n = 11).” (opens the source at this quote in a new tab)

Study outcomes
Rationale for using MDS-UPDRS part III score as the primary endpoint
Primary endpoint definition

“The primary study endpoint was the change, from baseline, in MDS-UPDRS Part III score at week 15.” (opens the source at this quote in a new tab)

“MDS-UPDRS Part III scores were also compared between treatment groups at weeks 3, 5, 7, 9, and 12.” (opens the source at this quote in a new tab)

Efficacy threshold derived from the minimal clinically important difference

“The target MDS-UPDRS Part III efficacy threshold for PF-06649751 (change from baseline relative to placebo) in the current trial was 3.6 points, and was based on an internal meta-analysis of historical studies in subjects with early Parkinson’s disease, which utilized the traditional Unified Parkinson’s Disease Rating Scale (UPDRS). The minimal clinically important difference in traditional UPDRS Part III score is considered to be approximately 2.5 points.” (opens the source at this quote in a new tab)

“Therefore, we sought to set our efficacy criteria as PF-06649751 having at least a 3 point improvement over placebo in traditional UPDRS Part III score after 15 weeks of treatment. This corresponds to an improvement of at least 3.6 points in the newer MDS-UPDRS Part III.” (opens the source at this quote in a new tab)

Safety and exploratory outcome measures

“Safety and tolerability measures included AE reporting, clinical laboratory parameters, vital signs, ECG parameters, the Beck Depression Inventory-II (BDI-II), Epworth Sleepiness Scale (ESS), the Columbia Suicide Severity Rating Scale (C-SSRS), the Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS), and the Physician Withdrawal Checklist (PWC-20).” (opens the source at this quote in a new tab)

“Change, from baseline, in exploratory endpoint measures was assessed at weeks 9 and 15, and included Patient Global Impression-Severity (PGI-S), Patient Global Impression-Improvement (PGI-I), Parkinson’s Disease Questionnaire (PDQ-39), EuroQol 5 Dimension (EQ-5D-5L), Oral Symbol Digit Modality Test (OSDMT), Modified Clinical Global Impression-Severity (MCGI-S), Modified Clinical Global Impression-Improvement (MCGI-I), and MDS-UPDRS total and component scores.” (opens the source at this quote in a new tab)

Statistical analysis description
Number of participants (Planned and analyzed)
Sample size and decision criteria

“The decision criteria for efficacy were: (1) a ⩾50% confidence that the PF-06649751 effect is at least 3.6 points better than placebo (i.e. a mean improvement of at least 3.6 points over placebo), and (2) a ⩾95% confidence that the PF-06649751 effect over placebo is greater than 0.” (opens the source at this quote in a new tab)

“It was estimated that 34 subjects per arm would give sufficient precision to meet both criteria, and, assuming that 23% of subjects would fail to complete the study or optimize the dose, 44 subjects per arm were planned.” (opens the source at this quote in a new tab)

Participants randomized against the planned sample

“Overall, 57 subjects were enrolled instead of the 88 that were planned.” (opens the source at this quote in a new tab)

Description of analysis sets
Full Analysis Set and statistical model

“All efficacy analyses were based on the Full Analysis Set, defined as all subjects who received at least one dose of study medication and had baseline and at least one post-baseline MDS-UPDRS Part III score.” (opens the source at this quote in a new tab)

“Efficacy comparisons for this model were based on the treatment difference versus placebo using least squares means and hypothesis testing utilized a one-sided α of 0.05, corresponding to a statistical significance threshold of p < 0.1 in two-sided values.” (opens the source at this quote in a new tab)

Results
Participant disposition
Early termination linked to the companion trial in advanced Parkinson's disease

“This study was terminated early. However, the decision to terminate was not based on, and did not consider, data from the study itself. Prior to the start of this study, a strategic linkage was established with a concurrent study in more advanced PD (ClinicalTrials.gov NCT02687542). When the interim analysis of data from the more advanced PD study showed a low probability that it would reach a target efficacy threshold, (which was not a comparison with placebo, but a more stringent placebo-adjusted target value) that study was terminated, triggering a decision to terminate this trial early as well.” (opens the source at this quote in a new tab)

Registry statement of the reason for termination

“Study B7601011 was terminated on 29 Jan 2018 due to lack of efficacy in moderate/advanced Parkinson's disease.” (opens the source at this quote in a new tab)

Randomized, treated, and completing participants

“Overall, 57 subjects were randomized and received study treatment (placebo = 28 and PF-06649751 = 29; Figure 2). Of these, 22 (78.6%) and 25 (86.2%) completed the study in the placebo and PF-06649751 groups, respectively.” (opens the source at this quote in a new tab)

“The number of subjects reaching the dose maintenance phase was 22 (78.6%) in the placebo group and 26 (89.7%) in the PF-06649751 group.” (opens the source at this quote in a new tab)

Baseline characteristics
Demographics and baseline disease characteristics
CharacteristicPlacebo (n = 28)PF-06649751 (n = 29)
Age, years, mean (SD)“63.36 (9.16)”“64.76 (8.34)”
Female, n (%)“14 (50.0)”“9 (31.0)”
White, n (%)“25 (89.3)”“28 (96.6)”
Duration since Parkinson's disease onset, years, mean (SD)“1.61 (1.92)”“1.42 (1.73)”
Baseline MDS-UPDRS Part III score, mean (SD)“25.8 (10.5)”“23.9 (12.3)”
Concomitant Parkinson's disease medication

“Overall, 16/29 subjects in the PF-06649751 group and 16/28 subjects in the placebo group received concomitant medication to treat PD symptoms. The medications most frequently taken were rasagiline/rasagiline mesylate (taken by 13/29 subjects in the PF-06649751 group and by 10/28 subjects in the placebo group) and amantadine (taken by 4/29 subjects in the PF-06649751 group and 6/28 subjects in the placebo group).” (opens the source at this quote in a new tab)

Efficacy results
Primary endpoint: change in MDS-UPDRS Part III score at week 15

“The PF-06649751 group exhibited a mean (SE) change, from baseline to week 15, in MDS-UPDRS Part III score of −9.0 (1.54) compared with −4.3 (1.65) for placebo (Figure 3). This corresponds to a least squares mean (SE) (90% CI) improvement over placebo of 4.8 (2.26) (1.0, 8.6) for the PF-06649751 group (2-sided p = 0.0407). PF-06649751, therefore, met the first predefined efficacy criteria by demonstrating an observed mean treatment effect over placebo of greater than 3.6 points. The probability that this observed treatment effect over placebo was greater than 0 was determined to be 98%; thus, PF-06649751 also met the second prespecified primary efficacy criteria and the overall primary endpoint.” (opens the source at this quote in a new tab)

Onset of effect by week 3

“Statistically significant improvements in MDS-UPDRS Part III scores were also evident in the PF-06649751 group, compared with placebo, at all timepoints prior to week 15 (weeks 3, 5, 7, 9, and 12; all 2-sided p < 0.1; Figure 3).” (opens the source at this quote in a new tab)

Exploratory endpoints: combined MDS-UPDRS scores and other scales

“Exploratory analyses demonstrated statistically significant (2-sided p < 0.1) improvements in combined MDS-UPDRS scores (Part II + III, Part I + II + III, and total) at all timepoints assessed (weeks 9 and 15) in the PF-06649751 group compared with placebo (data not shown), driven in large part by changes in MDS-UPDRS Part III score.” (opens the source at this quote in a new tab)

“However, there was no statistically significant difference between treatment groups for any of the following scales at weeks 9 and 15: MDS-UPDRS Part I, MDS-UPDRS Part II, PDQ-39 global score, EQ-5D-5L, OSDMT, MCGI-I, MCGI-S, and PGI-S (all data not shown).” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes
Patient Global Impression of Improvement

“Exploratory assessment of PGI-I scores at weeks 9 and 15 demonstrated statistically significant improvement (lower score) in the PF-06649751 group compared with placebo. Mean/median PGI-I scores were 3.0/3.0 in the PF-06649751 group at week 9 compared with 3.5/4 for placebo (2-sided p = 0.055) and 2.5/2.0 in the PF-06649751 group at week 15 compared with 3.2/3.5 for placebo (2-sided p = 0.039).” (opens the source at this quote in a new tab)

Parkinson's Disease Questionnaire and EuroQol 5 Dimension

“there was no statistically significant difference between treatment groups for any of the following scales at weeks 9 and 15: MDS-UPDRS Part I, MDS-UPDRS Part II, PDQ-39 global score, EQ-5D-5L, OSDMT, MCGI-I, MCGI-S, and PGI-S (all data not shown)” (opens the source at this quote in a new tab)

Safety results
Summary of adverse events
MeasurePlacebo (n = 28)PF-06649751 (n = 29)
Participants with at least 1 all-causality AE, n (%)“18 (64.3)”“25 (86.2)”
Participants with at least 1 treatment-related AE, n (%)“10 (35.7)”“22 (75.9)”
Participants with at least 1 serious AE, n (%)“0”“1 (3.4)”
Participants discontinued due to AE, n (%)“4 (14.3)”“2 (6.9)”
Deaths, n (%)“0”“0”
Most common adverse events
Adverse eventPlacebo (n = 28), n (%)PF-06649751 (n = 29), n (%)
Nausea“2 (7.1)”“9 (31.0)”
Headache“2 (7.1)”“7 (24.1)”
Dry mouth“0”“5 (17.2)”
Somnolence“1 (3.6)”“4 (13.8)”
Tremor“2 (7.1)”“4 (13.8)”
Hypotension“0”“2 (6.9)”
Dizziness“1 (3.6)”“2 (6.9)”
Serious adverse event: suicidal ideation

“One serious AE (suicidal ideation) occurred in a subject in the PF-06649751 group. This event started and resolved on day 64, but led to study discontinuation on day 70.” (opens the source at this quote in a new tab)

Blood pressure and orthostatic hypotension

“More subjects treated with PF-06649751 met categorization criteria for standing diastolic BP decrease of ⩾20 mmHg (8 versus 2), standing systolic BP decrease ⩾30 mmHg (4 versus 1), supine diastolic BP decrease ⩾20 mmHg (9 versus 1), and supine systolic BP decrease ⩾30 mmHg (5 versus 0) than subjects treated with placebo. Regarding orthostatic hypotension, there was a difference between treatment groups for the incidence of diastolic BP postural difference >10 mmHg (3 for PF-06649751 versus 1 for placebo) and there was no apparent increase in orthostatic hypotension-related AEs such as dizziness, fainting, or lightheadedness. No subjects met criteria for significant ECG changes.” (opens the source at this quote in a new tab)

Sleepiness, impulse control, depression, suicidality, and withdrawal scales

“There was no apparent difference between treatment groups on the BDI-II, ESS, QUIP-RS, C-SSRS, and PWC-20 at weeks 9 and 15 (data not shown).” (opens the source at this quote in a new tab)

Laboratory safety

“There were no clinically meaningful effects of PF-06649751, relative to placebo, for standard laboratory safety assessments, including blood chemistry and liver function.” (opens the source at this quote in a new tab)

Study limitations
Summary: limitations of the NCT02847650 evidence

Enrollment stopped early after a linked phase 2 trial in advanced Parkinson's disease (NCT02687542) met futility criteria at an interim analysis, so 57 of the 88 planned participants were randomized (29 to PF-06649751 and 28 to placebo). Efficacy testing used a one-sided alpha of 0.05, equivalent to a two-sided threshold of p < 0.1, and the primary result was reported with a 90% confidence interval of 1.0 to 8.6 points. The double-blind period was 15 weeks. The PF-06649751 group had a lower proportion of women (31.0%) than the placebo group (50.0%). Maintenance doses ranged from 0.75 mg to 15 mg, with 11 participants maintained on 15 mg. Most exploratory scale results were reported as data not shown.

Limitations stated by the authors

“Though PF-06649751 met the primary efficacy endpoint, some limitations of the study should be noted. Foremost, enrollment in the study was terminated early by the sponsor. Overall, 57 subjects were enrolled instead of the 88 that were planned.” (opens the source at this quote in a new tab)

“It should be noted that, although PF-06649751 consistently and significantly improved MDS-UPDRS Part III scores during the current trial, the trial was focused on subjects with early stage Parkinson’s disease and there remains a need to assess the safety and efficacy of PF-06649751 in other stages of the disease.” (opens the source at this quote in a new tab)