NCT02373072

21 evidence topics · 4 sources

Objective

Trial objective: single ascending doses in idiopathic Parkinson's disease

“A Phase 1, Double Blind, Sponsor Open, Randomized, Placebo-controlled, Single Ascending Dose Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-06649751 In Subjects With Idiopathic Parkinson's Disease” (opens the source at this quote in a new tab)

Study summary

“This is a study with two sequential cohorts, each with three treatment periods. Single doses of PF-06649751 will be tested in this study, starting at a low dose and escalating to a dose projected to be under the current limits for drug concentration. Each cohort will aim to achieve approximately 9 completers. Primary endpoint is safety and tolerability, secondary endpoint is MDS-UPDRS part III.” (opens the source at this quote in a new tab)

Location and study date

Summary: sponsor, identifiers, and study dates

The registry record for NCT02373072 gives Pfizer as sponsor and B7601009 as the sponsor study number. The study started in March 2015, reached primary completion in February 2016, and was completed in March 2016, with 18 participants enrolled. No results have been posted to the registry.

Study sites

“A single ascending dose (SAD) study (NCT02373072) was conducted at five sites in the USA and one site in Belgium” (opens the source at this quote in a new tab)

Study design

Randomized, placebo-substitution, three-way crossover design

“The SAD study was a randomized, double-blind, sponsor-open, placebo-controlled, placebo-substitution study with three-way crossover design in subjects with idiopathic Parkinson’s disease (Table 1). After overnight washout of l-dopa (no l-dopa administration after 8 PM), study drug or placebo was administered once during each of three treatment periods, with an at least 7-day study drug washout phase between treatment periods.” (opens the source at this quote in a new tab)

Eligibility criteria

Inclusion and exclusion criteria

“Both the SAD and MAD studies admitted male or female subjects of non-childbearing potential between the ages of 30 and 85 years (SAD study) or 30 and 80 years (MAD study), inclusive, with a body mass index of 17.5–38.0 kg/m2 and a total body weight greater than 50 kg, and with a clinical diagnosis of idiopathic Parkinson’s disease, including the presence of at least two out of three cardinal characteristics (tremor, rigidity, and/or bradykinesia).” (opens the source at this quote in a new tab)

Treatment

Doses by cohort

“PF-06649751 doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg.” (opens the source at this quote in a new tab)
“All subjects in cohort 1 period 1 received either PF-06649751 (0.75 mg) or placebo, and dosing proceeded through two additional periods as outlined in Table 1.” (opens the source at this quote in a new tab)
“All subjects in cohort 2 received either a higher starting dose of PF-06649751 (3 mg) or placebo, and dosing for cohort 2 proceeded as outlined in Table 1.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using adverse events as the primary endpoint

Primary and secondary outcome measures

“Number and proportion of subjects with Adverse Events (AEs)” (opens the source at this quote in a new tab)
“Number of participants with ECG data that meet criteria of potential clinical concern” (opens the source at this quote in a new tab)
“MDS - Unified Parkinson's Disease Rating Scale Part III” (opens the source at this quote in a new tab)

Central rating of the MDS-UPDRS Part III

“All Part III assessments were performed by the local rater and, in the SAD study, rating sessions were video-recorded for evaluation by an independent central qualified rater.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Participants randomized and completing

“In the SAD study, a total of 18 subjects were randomized and assigned to study treatments. All subjects completed the treatment, except for one subject from cohort 2 who discontinued after two periods as they were no longer willing to participate.” (opens the source at this quote in a new tab)

Description of analysis sets

Mixed-model analysis of MDS-UPDRS Part III

“In the SAD study, change from baseline in MDS-UPDRS-III total score was analyzed using a restricted maximum likelihood linear mixed-effect repeated measures model with fixed effects for treatment, time (visit), baseline MDS-UPDRS-III total motor score, and a random effect for subject.” (opens the source at this quote in a new tab)
“All subjects treated with study drugs were analyzed for pharmacodynamics and safety.” (opens the source at this quote in a new tab)

Results

Participant disposition

Discontinuation

“All subjects completed the treatment, except for one subject from cohort 2 who discontinued after two periods as they were no longer willing to participate.” (opens the source at this quote in a new tab)

Baseline characteristics

Sex, race, age, weight, and body mass index

“The majority of the subjects were male (15/18) and white (16/18). The mean age (60.1 years, range 44–76 years), mean weight (81.0 kg, range 56.1–126.6 kg), and body mass index (27.8 kg/m2, range 18.3–37.5 kg/m2) were generally comparable across the two cohorts (Supplementary Table 1).” (opens the source at this quote in a new tab)

Efficacy results

Change in MDS-UPDRS Part III total score after a single 9 mg dose

“In the SAD study, there was a statistically significant (p < 0.05) decrease in least squares (LS) mean change from baseline in MDS-UPDRS-III total motor score on day 1 at 1, 2, 4, 8, and 12 h in subjects in the PF-06649751 9-mg treatment group compared with placebo (Fig. 1). At 12 h post dose the LS mean change of MDS-UPDRS-III scores from baseline was –0.82 ± 3.26 (90% CI, –6.35, 4.71) and –11.96 ± 4.16 (90% CI, –18.88, –5.03) for placebo and PF-06649751 9 mg, respectively. The MDS-UPDRS-III demonstrated a statistically significant difference of –11.13 ± 3.68 (90% CI, –17.21, –5.06; p = 0.0028) in the PF-06649751 9-mg treatment group versus placebo.” (opens the source at this quote in a new tab)

Single 3 mg dose

“Similarly, there were greater decreases from baseline in LS mean total motor score on day 1 at 1, 2, 4, 8, and 12 h in subjects in the PF-06649751 3-mg treatment group versus placebo; however, the differences were not statistically significant.” (opens the source at this quote in a new tab)

Single-dose pharmacokinetics

“Following administration of single oral doses of PF-06649751 from 0.75 mg to 9 mg under fasted conditions, PF-06649751 Cmax occurred at approximately 3.0–4.0 h post dose (Supplementary Fig. 1 top panel and Supplementary Table 3). The half-life (t1/2) of PF-06649751 for the 3-mg group in cohort 2 was approximately 16 h.” (opens the source at this quote in a new tab)
“Both peak exposure (Cmax) and total exposure (AUClast) increased with increasing dose from 0.75 mg to 9 mg, and the increases appeared to be dose proportional as evidenced by similar dose-normalized AUClast and Cmax across all doses.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Adverse events

“In the SAD study, single doses of PF-06649751 up to 9 mg were safe and well tolerated by subjects with Parkinson’s disease. There were no deaths, serious AEs (SAE), severe AEs, discontinuations due to AEs, dose reductions, or temporary discontinuations due to AEs. A total of 46 all-causality treatment-emergent AEs (TEAEs) were reported, of which 35 were considered treatment related. All TEAEs were mild to moderate in severity (Supplementary Table 5). The most common TEAEs across all groups were headache, nausea, and vomiting (Supplementary Table 6).” (opens the source at this quote in a new tab)

QTcF changes after single doses

“There appeared to be a small dose-related increase in QT interval corrected for heart rate using Fridericia’s formula (QTcF) at the 2, 4, and 8 h post dose time points. The greatest increase from baseline in mean QTcF at any time point for any dose group was 11.7 ms.” (opens the source at this quote in a new tab)
“The reason for observed QTcF changes following single doses requires further investigation as PF-06649751 is expected to interact minimally with hERG (potassium ion) channels at clinically relevant concentrations.” (opens the source at this quote in a new tab)

Nausea and vomiting in healthy volunteer studies

“Healthy subject studies (single and multiple dose studies) with PF-06649751 were associated with nausea and vomiting, even at low doses, precluding evaluation of safety at projected clinically relevant doses (data on file).” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of the NCT02373072 evidence

The study enrolled 18 participants, gave single doses only, and assessed MDS-UPDRS Part III after an overnight levodopa washout, so it provides no information on repeated dosing or on use adjunctive to levodopa. The statistically significant motor effect was limited to the 9 mg dose, and the 3 mg dose did not differ significantly from placebo. Pharmacodynamic comparisons used 90% confidence intervals. The terminal half-life could not be characterized for most doses. No results have been posted to the registry.

Half-life characterization

“The t1/2 was not reportable for most treatments because the data were not sufficient for adequate characterization of the elimination phase.” (opens the source at this quote in a new tab)