2.2 Phase I/IIa clinical study
2.2.1 Subjects
To be eligible to participate in the Phase I clinical study male and
female subjects were required to be aged 25 years and above, with no
previous exposure to serotonergic psychedelic substances, and registered
with a general practitioner within the UK. Subjects were also required
to have a body mass index (BMI) 18.0–30.9 kg/m2, no
clinically relevant physical findings, electrocardiogram (ECG) or
clinical laboratory parameters at the screening visit.
Subjects with a current or past diagnosis of a mental health disorder as
defined by the American Psychiatric Association Diagnostic and
Statistical Manual of Mental Disorders, fifth edition (DSM-5), a history
of suicide attempts, or any first- or second-degree relative with a
psychotic or bipolar disorder were excluded from the study.
2.2.2 Study design and treatment
The Phase I study was a randomised, double-blind, placebo-controlled,
parallel-group dose-escalation trial (ClinicalTrials.gov: NCT04673383;
EudraCT: 2020-000251-13). The study was conducted to meet criteria of
European Medicines Agency (EMA) guidelines and Good Clinical Practice.
The study was approved by the UK Medicines and Healthcare Products
Regulatory Agency (MHRA) and London Brent ethics committee.
Due to the psychedelic effects of DMT and the absence of comprehensive
safety and tolerability data from previous clinical studies, EMA
guidelines for risk identification and risk mitigation were
followed,22 together with scientific advice from the
MHRA. Additionally, the study was designed in accordance with published
guidelines regarding the clinical assessment of hallucinogenic
substances in humans.23
At the screening visit, subjects provided written informed consent and
attended a structured interview with the study psychiatrist using the
Mini-International Neuropsychiatric Interview. All subjects participated
in individual or group preparation sessions, including advice on what to
expect and how to respond to the psychedelic experience at screening and
again the day prior to study drug administration.
Subjects were admitted to the clinical pharmacology unit (Hammersmith
Medicines Research [HMR], London, UK) the day before study drug
administration. No intake of alcohol or caffeine for 24 hours before and
during the treatment period was permitted. On the day of treatment,
study drug was administered in a room set up according to best practice
principles for psychedelic studies,23 including soft
lighting, soft furnishings, music and photographs/art depicting scenes
of nature; subjects were also asked to wear an eye mask during study
drug administration. A therapist and a psychiatrist were present in the
room, with additional clinical staff supervising study drug
administration and blood sampling.
Subjects were required to remain in the clinical unit overnight for
further psychological and safety evaluations and discharged the next
morning dependent on satisfactory assessment outcomes. Follow-up was
conducted by phone or video call for up to 3 months after study
treatment.
Four single ascending dose levels of SPL026 were studied, dependent on
tolerability and the PK profile of each dose. Further details of the
clinical study and psychotherapy methodology will be published
elsewhere.
SPL026 drug substance and drug product were manufactured in the UK in
accordance with Good Manufacturing Practice (GMP) with 2.5 mg/mL DMT
free base in 10 ml aqueous sterile solution; placebo consisted of the
same ingredients and volume with the exception of the active substance.
Active and placebo treatments were identical in appearance and
administered in the same volume.
2.2.3 Dosing procedure
Study drug was administered as a continuous 10-minute IV infusion, split
into 2 phases. A single cannula was inserted in the forearm vein with
two separate syringes and two separate syringe pumps, connected by a
3-way tap in order to provide different infusions rates for the 2 phases
of infusion. The first syringe pump infused study drug over 5 minutes
(Phase 1), followed by another 5-minute infusion from the second syringe
pump (Phase 2).
There were 4 dosing regimens of SPL026 (Table 1) and each dose cohort
was randomised so that 6 subjects received SPL026 and 2 placebo (doses
are stated as free base DMT unless otherwise indicated). Following the
completion of each dose level, the infusion regimen for the next dose
level was assessed according to PK modelling (described below).
2.2.5 PK modelling
The dosing regimen used in this study was selected based on PK modelling
with the aim of generating a slower onset of the psychedelic experience,
whilst achieving the same peak plasma concentrations attained in
previous clinical studies. A one-compartment model was determined to
best describe the PK of IV administered DMT fumarate
data.22,23 The resulting model parameters were used to
simulate multiple infusion regimens of total DMT doses ranging from
9–21.5 mg. Each infusion regimen comprised a 6 mg dose given over the
first 5 min to support the intent of a gradual onset of psychedelic
experience, followed by a second infusion designed to elicit further
psychedelic effects (see the Supplementary Information for full
details). Simulated PK profiles and associated peak plasma concentration
(Cmax) predictions are presented in Figure S1 and Table
S2.
The plasma concentration data from Cohorts 1, 2 and 4 were also modelled
using a one-compartment infusion model. The model was considered an
appropriate fit for the individual plasma-concentration data from Cohort
1 (mean parameter errors <15%), Cohort 2 (mean parameter
errors <20%) and Cohort 4 (mean parameter errors
<20%) (Table S2, Table S3). The resulting mean dataset
parameters were used to generate predictions at different infusion times
and rates prior to dose escalation (Figure S2). Cohort 3 data was deemed
inappropriate for such modelling due to multiple missing samples
(described in the Results section).
Compartmental and simulated PK analyses were conducted using PCModfit
version 6.9 for Windows running with Microsoft Excel
(2019).24
2.2.6 PK
Blood samples were drawn using a cannula inserted in the forearm vein
(the opposite side to where study treatment was administered) pre-dose
and at a nominal 2, 5, 6, 7, 10 (end of IV infusion), 11, 13, 15, 30,
60, 120 and 240 min after the start of the infusion.
Plasma concentrations at actual timepoints for each subject were
analysed. The following PK parameters were calculated using all
available data for each evaluable subject: Cmax; time to
peak plasma concentration (Tmax), area under the plasma
concentration–time curve from time zero to time of last measurable
concentration (AUClast); area under the plasma
concentration–time curve from time zero to infinity
(AUCinf); terminal half-life (t1/2);
clearance (CL); apparent volume of distribution during terminal phase
after IV administration (Vz); volume of distribution at
steady state after IV administration (Vss); and mean
residence time after IV administration (MRTinf).
Determination of SPL026 and IAA in human plasma was conducted using a
validated ultra high-performance LC-MS/MS system (Pharmaron UK Ltd.,
Hoddesdon, UK). The internal standard used for DMT was
DMT-d8 and control blank was human plasma
(K2EDTA; BiolVT Ltd.). The calibration range to be
validated for DMT was 0.0619 ng/mL (lower limit of quantification
[LLOQ]) to 310 ng/mL, and 2.00–1000 ng/mL for IAA.
2.2.7 Statistical analyses
The PK concentration population comprised subjects who received at least
1 dose of study treatment and for whom a blood sample had been analysed.
The PK parameter population comprised subjects in the PK concentration
population for whom PK parameters could be derived.
Actual sampling times were used to derive PK parameters and missing data
were not imputed. Plasma concentrations of DMT below LLOQ of the
LC-MS/MS were either treated as zero (if they occurred before
Tmax) or considered as missing.
Plasma concentrations and PK parameters were summarised by treatment,
using descriptive statistics. For log-transformed parameters, the
primary measure of central tendency was the geometric mean and other
parameters, it was the arithmetic mean or median.
Dose proportionality was assessed using analysis of variance (ANOVA),
linear regression and the power model for Cmax and
AUClast parameters. Dose-normalised and log-transformed
PK parameters were compared between dose cohorts using one-way ANOVA.
The linearity between log transformed Cmax, and
AUClast vs SPL026 was determined25using a linear regression model, setting the administered dose as the
independent variable and each PK parameter as the dependent variable.
The linear relationship between Cmax and
AUClast dose were assessed using the power model (log PK
parameter = α + β * log(dose) + ε), where α=intercept, β=slope. The
power model was fitted by restricted maximum likelihood (REML) mixed
effect model, with intercept and log(dose) as fixed effects. The dose
proportionality of each PK parameter was confirmed if the 90%
confidence interval (CI) of β (log PK parameter vs log dose) included
the value 1.0.
The relationship between BMI, weight and age vs dose-normalised
Cmax and concentration at 5 minutes
(C5min) was determined by linear regression analysis to
confirm that flat dosing (rather than weight-based dosing) of SPL026 was
appropriate.
PK analysis was conducted by the Statistics and Data Management
Department at HMR, using WinNonlin version 8.1 or higher. Descriptive
statistics were derived using SAS version 9.4 or higher, including mean,
standard deviation (SD), median, minimum and maximum values.
Additionally, for PK variables percent coefficient of variation (%CV)
and 95% CI of the arithmetic mean were derived. The adjusted
coefficient of determination (R2) measured the
goodness-of-fit for the linear regression model (where values range from
0-1, 0 indicating that the predictor variable accounts for no variation
in the dependent variable, and 1 predictor variable accounts for all
variation in dependent variable values). Post-hoc analyses were
performed using IBM SPSS version 28.0 and tested at the p<0.05
significance level.