NCT02526160

Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)

Completed Phase 3 Results posted Last updated 18 June 2024

What this trial tests

Phase 3 trial testing burosumab in X-linked Hypophosphatemia in 134 participants. Completed in 6 December 2018.

Timeline

22 October 2015

Primary endpoint
22 December 2016

6 December 2018

Quick facts

Lead sponsor	Kyowa Kirin, Inc.
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	quadruple
Primary purpose	treatment
Enrollment	134
Start date	22 October 2015
Primary completion	22 December 2016
Estimated completion	6 December 2018
Sites	25 locations across France, Italy, Japan, Ireland, United Kingdom, South Korea, United States

Drugs / interventions tested

• burosumab (BUROSUMAB) — full drug profile →
• Placebo

Conditions studied

• X-linked Hypophosphatemia — all drugs for X-linked Hypophosphatemia →

Sponsor

Kyowa Kirin, Inc. — full company profile →

Who can join

Adults 18 to 65, any sex, with X-linked Hypophosphatemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN (2.5 mg/dL [0.81 mmol/L]) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 Primary · Baseline through Week 24

Group	Value	95% CI
Placebo	7.6	3.3 – 16.5
Burosumab	92.6	83.9 – 96.8

Change From Baseline to Week 24 in Brief Pain Inventory (BPI) Question 3 (Q3; Worst Pain in Past 24 Hours) Score Secondary · Baseline, 24 weeks

The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). From the generalized estimating equation (GEE) model, which includes the change from Baseline for the endpoint of interes

Group	Value	95% CI
Placebo	-0.32	± 0.222
Burosumab	-0.79	± 0.211

Change From Baseline to Week 24 in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness Score Secondary · Baseline, 24 weeks

The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE estimates are from the GEE model which includes the change from baseline for WOMAC Stiffn

Group	Value	95% CI
Placebo	0.46	± 3.139
Burosumab	-7.85	± 3.034

Change From Baseline to Week 24 in the WOMAC Physical Function Score Secondary · Baseline, 24 weeks

The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Physic

Group	Value	95% CI
Placebo	1.79	± 2.722
Burosumab	-3.11	± 2.553

Change From Baseline Over Time in BPI Worst Pain Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96

Change from baseline to post-baseline visits in BPI-Q3 (Worst Pain) score as averaged from daily diary scores recorded over 1 week and the study visit score. The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Question 3 of the short-form BPI (BPI-Q3) asks subjects to rate their pain at its worst in the last 24 hours on a scale of 0 (no pain) to 1

Change at Week 12

Group	Value	95% CI
Placebo	-0.37	± 0.216
Burosumab 1 mg/kg	-0.62	± 0.208

Change at Week 24

Group	Value	95% CI
Placebo	-0.31	± 0.242
Burosumab 1 mg/kg	-0.77	± 0.228

Change at Week 36

Group	Value	95% CI
Placebo	-1.25	± 0.234
Burosumab 1 mg/kg	-0.95	± 0.228

Change at Week 48

Group	Value	95% CI
Placebo	-1.49	± 0.243
Burosumab 1 mg/kg	-1.05	± 0.230

Change at Week 72

Group	Value	95% CI
Placebo	-1.28	± 0.283
Burosumab 1 mg/kg	-1.21	± 0.316

Change at Week 96

Group	Value	95% CI
Placebo	-0.99	± 0.265
Burosumab 1 mg/kg	-1.48	± 0.299

Change From Baseline Over Time in BPI Pain Severity Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96

Change from baseline to post-baseline visits in BPI pain severity score as averaged from daily diary scores recorded over 1 week and the study visit score. The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). The severity of pain in the last 24 hours is rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The GEE Estimates are f

Change at Week 12

Group	Value	95% CI
Placebo	-0.32	± 0.166
Burosumab 1 mg/kg	-0.43	± 0.163

Change at Week 24

Group	Value	95% CI
Placebo	-0.10	± 0.211
Burosumab 1 mg/kg	-0.53	± 0.172

Change at Week 36

Group	Value	95% CI
Placebo	-0.97	± 0.214
Burosumab 1 mg/kg	-0.62	± 0.184

Change at Week 48

Group	Value	95% CI
Placebo	-1.13	± 0.205
Burosumab 1 mg/kg	-0.79	± 0.162

Change at Week 72

Group	Value	95% CI
Placebo	-1.36	± 0.216
Burosumab 1 mg/kg	-1.24	± 0.231

Change at Week 96

Group	Value	95% CI
Placebo	-1.18	± 0.195
Burosumab 1 mg/kg	-1.42	± 0.229

Change From Baseline Over Time in BPI Pain Interference Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96

Change from baseline to post-baseline visits in BPI pain interference score as recorded on the day of the study visit. The BPI evaluates the condition of all pain over the previous 24 hours. Two dimensions are measured: pain severity (worst, least, average, and now) and the impact of pain on functioning (pain interference with general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Pain interference in the last 24 hours is rated on a scale of 0 (does not interfere) to 10 (completely interferes). The GEE Estimates are from the GEE model which includes the c

Change at Week 12

Group	Value	95% CI
Placebo	-0.29	± 0.215
Burosumab 1 mg/kg	-0.51	± 0.207

Change at Week 24

Group	Value	95% CI
Placebo	-0.28	± 0.242
Burosumab 1 mg/kg	-0.41	± 0.207

Change at Week 36

Group	Value	95% CI
Placebo	-1.30	± 0.260
Burosumab 1 mg/kg	-0.79	± 0.221

Change at Week 48

Group	Value	95% CI
Placebo	-1.28	± 0.251
Burosumab 1 mg/kg	-1.04	± 0.235

Change at Week 72

Group	Value	95% CI
Placebo	-1.22	± 0.247
Burosumab 1 mg/kg	-1.24	± 0.263

Change at Week 96

Group	Value	95% CI
Placebo	-1.08	± 0.260
Burosumab 1 mg/kg	-1.43	± 0.234

Change From Baseline Over Time in WOMAC Stiffness Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144

The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Stiffn

Change at Week 12

Group	Value	95% CI
Placebo	-1.24	± 2.929
Burosumab 1 mg/kg	-7.86	± 3.622

Change at Week 24

Group	Value	95% CI
Placebo	0.20	± 3.289
Burosumab 1 mg/kg	-8.01	± 2.968

Change at Week 36

Group	Value	95% CI
Placebo	-13.50	± 3.422
Burosumab 1 mg/kg	-12.58	± 3.411

Change at Week 48

Group	Value	95% CI
Placebo	-15.83	± 3.488
Burosumab 1 mg/kg	-16.63	± 3.302

Change at Week 72

Group	Value	95% CI
Placebo	-18.02	± 3.613
Burosumab 1 mg/kg	-15.47	± 3.111

Change at Week 96

Group	Value	95% CI
Placebo	-17.67	± 3.737
Burosumab 1 mg/kg	-15.32	± 3.577

Change at Week 120

Group	Value	95% CI
Placebo	-19.23	± 3.404
Burosumab 1 mg/kg	-20.57	± 3.371

Change at Week 144

Group	Value	95% CI
Placebo	-30.64	± 4.407
Burosumab 1 mg/kg	-25.88	± 4.501

Change From Baseline Over Time in WOMAC Physical Function Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96, 120, 144

The WOMAC is a 24-item participant-reported questionnaire with two domains, Stiffness (2 questions) and Physical Function (17 questions) over the previous 48 hours. The WOMAC is administered in a 5-point Likert-scale format using descriptors of none, mild, moderate, severe, and extreme corresponding to an ordinal scale of 0-4. Higher scores on the WOMAC indicate worse stiffness and functional limitations. Scores are normalized to a 0-100 metric where 0 was the best health state and 100 the worst. The GEE Estimates are from the GEE model which includes the change from baseline for WOMAC Stiffn

Change at Week 12

Group	Value	95% CI
Placebo	-1.40	± 2.418
Burosumab 1 mg/kg	-3.96	± 1.787

Change at Week 24

Group	Value	95% CI
Placebo	1.14	± 2.531
Burosumab 1 mg/kg	-3.45	± 2.193

Change at Week 36

Group	Value	95% CI
Placebo	-5.47	± 2.694
Burosumab 1 mg/kg	-7.14	± 2.133

Change at Week 48

Group	Value	95% CI
Placebo	-7.15	± 2.801
Burosumab 1 mg/kg	-8.42	± 2.057

Change at Week 72

Group	Value	95% CI
Placebo	-8.68	± 2.835
Burosumab 1 mg/kg	-8.66	± 2.523

Change at Week 96

Group	Value	95% CI
Placebo	-8.41	± 2.752
Burosumab 1 mg/kg	-9.02	± 2.270

Change at Week 120

Group	Value	95% CI
Placebo	-11.93	± 2.685
Burosumab 1 mg/kg	-11.98	± 2.291

Change at Week 144

Group	Value	95% CI
Placebo	-19.49	± 3.892
Burosumab 1 mg/kg	-17.67	± 4.061

Change From Baseline Over Time in BFI Worst Fatigue Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96

Change from baseline to post-baseline visits in Brief Fatigue Inventory Question 3 (Worst Fatigue in Past 24 Hours; BFI-Q3) as averaged from daily diary scores recorded over 1 week and the study visit score. The BFI is a self-reported questionnaire consisting of 9 items related to fatigue rated on a 0 to 10 numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). Participants are asked to rate their worst fatigue over the pa

Change at Week 12

Group	Value	95% CI
Placebo	-0.53	± 0.266
Burosumab 1 mg/kg	-0.44	± 0.261

Change at Week 24

Group	Value	95% CI
Placebo	-0.45	± 0.298
Burosumab 1 mg/kg	-0.65	± 0.280

Change at Week 36

Group	Value	95% CI
Placebo	-1.23	± 0.305
Burosumab 1 mg/kg	-0.90	± 0.271

Change at Week 48

Group	Value	95% CI
Placebo	-1.21	± 0.317
Burosumab 1 mg/kg	-0.99	± 0.295

Change at Week 72

Group	Value	95% CI
Placebo	-0.79	± 0.352
Burosumab 1 mg/kg	-0.58	± 0.309

Change at Week 96

Group	Value	95% CI
Placebo	-0.82	± 0.362
Burosumab 1 mg/kg	-0.75	± 0.306

Change From Baseline Over Time in BFI Global Fatigue Score Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96

Change from baseline to post-baseline visits in BFI global fatigue score, calculated by averaging all 9 BFI items as recorded on the day of the study visit. The BFI is a self-reported questionnaire consisting of 9 items related to fatigue that are rated on a numerical scale with a recall period of 24 hours. Two dimensions are measured: fatigue severity and the interference of fatigue on daily life (activity, mood, walking ability, work, relations with others, and enjoyment of life). BFI Global Fatigue score was calculated by averaging all 9 items on the BFI. Global scores range from 0 to 10, w

Change at Week 12

Group	Value	95% CI
Placebo	-0.14	± 0.262
Burosumab 1 mg/kg	-0.18	± 0.261

Change at Week 24

Group	Value	95% CI
Placebo	-0.08	± 0.292
Burosumab 1 mg/kg	0.05	± 0.261

Change at Week 36

Group	Value	95% CI
Placebo	-0.69	± 0.315
Burosumab 1 mg/kg	-0.54	± 0.283

Change at Week 48

Group	Value	95% CI
Placebo	-0.75	± 0.303
Burosumab 1 mg/kg	-0.45	± 0.275

Change at Week 72

Group	Value	95% CI
Placebo	-0.72	± 0.304
Burosumab 1 mg/kg	-0.78	± 0.266

Change at Week 96

Group	Value	95% CI
Placebo	-0.86	± 0.291
Burosumab 1 mg/kg	-0.80	± 0.285

Change From Baseline Over Time in Biochemical Marker of Bone Remodeling Procollagen Type 1 N-Propeptide (P1NP) Secondary · Baseline, Weeks 12, 24, 36, 48, 72, 96

Change at Week 12

Group	Value	95% CI
Placebo	-1.86	± 5.958
Burosumab 1 mg/kg	96.22	± 14.264

Change at Week 24

Group	Value	95% CI
Placebo	2.95	± 6.423
Burosumab 1 mg/kg	63.50	± 7.239

Change at Week 36

Group	Value	95% CI
Placebo	100.00	± 10.562
Burosumab 1 mg/kg	49.71	± 6.786

Change at Week 48

Group	Value	95% CI
Placebo	85.12	± 11.037
Burosumab 1 mg/kg	40.07	± 7.292

Change at Week 72

Group	Value	95% CI
Placebo	48.98	± 7.286
Burosumab 1 mg/kg	18.04	± 9.186

Change at Week 96

Group	Value	95% CI
Placebo	22.98	± 7.075
Burosumab 1 mg/kg	12.48	± 8.661

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug through the end of study plus 4 weeks (+ 5 days). Mean (SE) duration of exposure to burosumab for all periods combined through EOS II was 771.3 (21.97) days (range: 167 - 957) in the burosumab->burosumab group and 625.7 (19.40) days (range: 165 - 844) in the placebo->burosumab group.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo (DB Period)

Serious: 1/66 (2%)

Deaths: 0/66

Placebo -> Burosumab (OL Period)

Serious: 10/66 (15%)

Deaths: 0/66

Burosumab -> Burosumab (Combined DB and OL Period)

Serious: 12/68 (18%)

Deaths: 1/68

Total Burosumab (Combined DB and OL Period)

Serious: 22/134 (16%)

Deaths: 1/134

Serious adverse events (35 terms)

Reaction	System	Placebo (DB Period)	Placebo -> Burosumab (OL P…	Burosumab -> Burosumab (Co…	Total Burosumab (Combined …
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Myelopathy	Nervous system disorders	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—
Duodenal Ulcer	Gastrointestinal disorders	—	—	—	—
Ileus	Gastrointestinal disorders	—	—	—	—
Irritable Bowel Syndrome	Gastrointestinal disorders	—	—	—	—
Periodontal Disease	Gastrointestinal disorders	—	—	—	—
Peritoneal Adhesions	Gastrointestinal disorders	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—
Medical Device Site Infection	Infections and infestations	—	—	—	—
Overdose	Injury, poisoning and procedural complications	—	—	—	—
Procedural Nausea	Injury, poisoning and procedural complications	—	—	—	—
Procedural Vomiting	Injury, poisoning and procedural complications	—	—	—	—
Road Traffic Accident	Injury, poisoning and procedural complications	—	—	—	—
Subdural Haematoma	Injury, poisoning and procedural complications	—	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Cervical Spinal Stenosis	Musculoskeletal and connective tissue disorders	—	—	—	—
Joint Range Of Motion Decreased	Musculoskeletal and connective tissue disorders	—	—	—	—
Knee Deformity	Musculoskeletal and connective tissue disorders	—	—	—	—
Musculoskeletal Pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—	—
Pseudarthrosis	Musculoskeletal and connective tissue disorders	—	—	—	—
Spinal Column Stenosis	Musculoskeletal and connective tissue disorders	—	—	—	—

Other adverse events (72 terms — click to expand)

Reaction	System	Placebo (DB Period)	Placebo -> Burosumab (OL P…	Burosumab -> Burosumab (Co…	Total Burosumab (Combined …
Nasopharyngitis	Infections and infestations	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—
Pain In Extremity	Musculoskeletal and connective tissue disorders	—	—	—	—
Tooth Abscess	Infections and infestations	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—
Vitamin D Deficiency	Metabolism and nutrition disorders	—	—	—	—
Musculoskeletal Pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Pain	General disorders	—	—	—	—
Restless Legs Syndrome	Nervous system disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Muscle Spasms	Musculoskeletal and connective tissue disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Vitamin D Decreased	Investigations	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Injection Site Reaction	General disorders	—	—	—	—
Influenza	Infections and infestations	—	—	—	—
Procedural Pain	Injury, poisoning and procedural complications	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—	—
Bone Pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—
Injection Site Erythema	General disorders	—	—	—	—
Joint Swelling	Musculoskeletal and connective tissue disorders	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Injection Site Pruritus	General disorders	—	—	—	—
Seasonal Allergy	Immune system disorders	—	—	—	—
Urinary Tract Infection	Infections and infestations	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—
Hypoaesthesia	Nervous system disorders	—	—	—	—
Nasal Congestion	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Abdominal Pain Upper	Gastrointestinal disorders	—	—	—	—

Most-reported serious reactions: Arthralgia, Myelopathy, Palpitations, Colitis, Duodenal Ulcer, Ileus, Irritable Bowel Syndrome, Periodontal Disease.

Data from ClinicalTrials.gov NCT02526160 adverse events section.

Sponsor's own description

The primary efficacy objective of this study is to establish the effect of burosumab treatment compared with placebo on increasing serum phosphorus levels in adults with XLH.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. FGF23 and its role in X-linked hypophosphatemia-related morbidity.
   Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, et al · · 2019 · cited 199× · PMID 30808384 · DOI 10.1186/s13023-019-1014-8
2. Antibodies to watch in 2018.
   Kaplon H, Reichert JM. · · 2018 · cited 179× · PMID 29300693 · DOI 10.1080/19420862.2018.1415671
3. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations.
   Chesher D, Oddy M, Darbar U, Sayal P, et al · · 2018 · cited 97× · PMID 29460029 · DOI 10.1007/s10545-018-0147-6
4. Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.
   Insogna KL, Rauch F, Kamenický P, Ito N, et al · · 2019 · cited 95× · PMID 31369697 · DOI 10.1002/jbmr.3843
5. Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension.
   Briot K, Portale AA, Brandi ML, Carpenter TO, et al · · 2021 · cited 54× · PMID 34548383 · DOI 10.1136/rmdopen-2021-001714
6. Musculoskeletal Features in Adults With X-linked Hypophosphatemia: An Analysis of Clinical Trial and Survey Data.
   Javaid MK, Ward L, Pinedo-Villanueva R, Rylands AJ, et al · · 2022 · cited 38× · PMID 34636401 · DOI 10.1210/clinem/dgab739
7. Benefit of burosumab in adults with X-linked hypophosphataemia (XLH) is maintained with long-term treatment.
   Kamenicky P, Briot K, Brandi ML, Cohen-Solal M, et al · · 2023 · cited 28× · PMID 36854566 · DOI 10.1136/rmdopen-2022-002676
8. Pharmacological management of X-linked hypophosphataemia.
   Imel EA, White KE. · · 2019 · cited 20× · PMID 30207609 · DOI 10.1111/bcp.13763