A placebo-controlled trial to investigate the safety and efficacy of Penicillin G/Hydrocortisone in patients with ALS (PHALS trial)

Figures & data

Figure 1. Study profile.

Table 1. Baseline characteristics.

Characteristic	PenGH	Placebo	Overall
	(N = 10)	(N = 6)	(N = 16)
Age (years.)	62 (7)	56 (12)	60 (9)
No. of males (%)	7 (70%)	5 (83%)	12 (75%)
No. of bulbar onset	6 (60%)	3 (50%)	9 (56%)
Diagnostic delay (mo.)	10 (4)	9 (4)	10 (4)
Symptom duration (mo.)	13 (4)	15 (5)	14 (4)
ALSFRS-R	38 (4)	39 (5)	39 (4)
ΔFRS (per mo.)	−0.76 (0.4)	−0.67 (0.47)	−0.73 (0.41)
SVC (%predicted)	94 (16)	81 (10)	89 (15)
Bodyweight (kg)	80 (12)	77 (12)	79 (12)
Body-mass index (kg/m^2)	25 (1)	24 (2)	25 (2)
ENCALS Risk Profile	−3.96 (0.84)	−4.19 (0.84)	−4.05 (0.82)

Data are in mean (SD) or n (%). ΔFRS is calculated as ALSFRS-R—48 / symptom duration (14). ENCALS Risk Profile is a prognostic summary score of eight prognostic variables (SVC, ΔFRS, diagnostic delay, site of onset, age of onset, presence of ALS-FTD, El Escorial classification and presence of C9orf72 repeat expansion) (11). Risk Scores range from approximately −12 to 0, where 0 indicates a poor prognosis and −12 an excellent prognosis (10).

Figure 2. Individual changes in ALSFRS-R total score since randomization. Individual patient ALSFRS-R total scores (y-axis) over time since randomization in months (x-axis). Prognosis is based on the ENCALS survival model (11).

Table 2. Primary and secondary efficacy endpoints.

Outcome	Placebo(n = 6)		PenGH (n = 10)		Mean difference
	Slope	95% CI	Slope	95% CI	Difference	95% CI (one-sided)	p
ALSFRS-R score	−2.7	−4.3 to −1.2	−2.2	−3.3 to −1.1	0.53	−1.01 to ∞	0.28
Bulbar	−0.5	−0.8 to −0.1	−0.5	−0.8 to −0.3	−0.10	−0.42 to ∞	–
Fine motor	−0.6	−1.1 to −0.2	−0.6	−1.0 to −0.3	−0.00	−0.46 to ∞	–
Gross motor	−0.6	−1.1 to −0.2	−0.6	−0.9 to −0.3	0.06	−0.36 to ∞	–
Respiratory	−0.9	−1.6 to −0.3	−0.4	−0.9 to 0.0	0.53	−0.12 to ∞	–
SVC %predicted	−5.8	−8.8 to −3.2	−2.9	−5.0 to −1.1	2.86	0.20 to ∞	–
HHD mega score	−14.7	−25.2 to −4.2	−11.5	−18.5 to −4.5	3.18	−7.25 to ∞	–
Plasma creatinine	−0.7	−1.4 to 0.0	−0.6	−1.0 to −0.1	0.10	−0.56 to ∞	–
Weight loss in kg	−0.8	−1.7 to −0.0	−0.0	−0.6 to 0.6	0.81	−0.02 to ∞	–
EQ-5D	−2.7	−6.6 to 1.3	−3.9	−6.7 to −1.2	−1.23	−5.23 to ∞	–

Monthly rates of change and the mean rate differences (penGH—placebo) estimated by linear mixed effects models, p-values are based on a one-sided likelihood ratio test. Due to the hierarchical testing procedure, p-values are not reported for the secondary endpoints. Abbreviations: ALSFRS-R: revised ALS functional rating scale; Bulbar domain: ALSFRS-R items 1–3; Fine domain: ALSFRS-R items 4–6; Gross domain: ALSFRS-R items 7–9; SVC: slow vital capacity; HHD: Hand-held dynamometry; EQ-5D: EuroQoL quality of life visual analogue scale.

Table 3. Safety profile.

System organ class	PenGH	Placebo
	(n = 10)	(n = 6)
Cardiac disorders	2 (20%)	1 (17%)
Eye disorders	1 (10%)	0 (0%)
Gastrointestinal disorders	8 (80%)	1 (17%)
General disorders and administration site conditions	3 (30%)	2 (33%)
Injury, poisoning and procedural complications	7 (70%)	4 (67%)
Line thrombosis	3 (30%)	3 (50%)
Investigations	4 (40%)	1 (17%)
Musculoskeletal and connective tissue disorders	5 (50%)	3 (50%)
Nervous system disorders	6 (60%)	4 (67%)
Psychiatric disorders	0 (0%)	1 (17%)
Renal and urinary disorders	5 (50%)	2 (33%)
Respiratory, thoracic and mediastinal disorders	7 (70%)	5 (83%)
Skin and subcutaneous tissue disorders	8 (80%)	4 (67%)
Vascular disorders	2 (20%)	1 (17%)

Number of patients (%). Adverse events were classified according to the Medical Dictionary for Regulatory Activities Terminology (MedDRA, version July 2018).

Figure 3. Propensity matched analysis of PHALS vs. PRO-ACT. Patients were matched 1:2 with placebo patients in the PRO-ACT cohort. The matched sample from PRO-ACT consisted of eligible patients for the PHALS criteria and complete data on all prognostic variables (N = 302). In the matched analysis, the mean difference in ALSFRS-R decline between PHALS and PRO-ACT was −1.03 points per month (−1.72 to −0.37, p = 0.003).

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