TSFAE04A

Subjects With Treatment-emergent Adverse Events Leading to Permanent Discontinuation of Study Treatment by System Organ Class, Preferred Term, and Subgroup

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Output

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# Program Name:              tsfae04a.R

# Prep Environment

library(envsetup)
library(tern)
library(dplyr)
library(rtables)
library(junco)

# Define script level parameters:

# - Define output ID and file location

tblid <- "TSFAE04a"
fileid <- tblid
tab_titles <- get_titles_from_file(input_path = '../../_data/', tblid)
string_map <- default_str_map


trtvar <- "TRT01A"
popfl <- "SAFFL"

subgrpvar <- "AGEGR1"
subgrptxt <- "Age Group"
subgrpunit <- "years"

combined_colspan_trt <- TRUE
risk_diff <- TRUE
rr_method <- "wald"
ctrl_grp <- "Placebo"

if (combined_colspan_trt == TRUE) {
  # Set up levels and label for the required combined columns
  add_combo <- add_combo_facet(
    "Combined",
    label = "Combined",
    levels = c("Xanomeline High Dose", "Xanomeline Low Dose")
  )

  # choose if any facets need to be removed - e.g remove the combined column for placebo
  rm_combo_from_placebo <- cond_rm_facets(
    facets = "Combined",
    ancestor_pos = NA,
    value = " ",
    split = "colspan_trt"
  )

  mysplit <- make_split_fun(post = list(add_combo, rm_combo_from_placebo))
}

# Process Data:

adsl <- pharmaverseadamjnj::adsl %>%
  filter(!!rlang::sym(popfl) == "Y") %>%
  mutate(
    subgrpdisplay = as.factor(paste0(
      subgrptxt,
      ": ",
      !!as.name(subgrpvar),
      " ",
      subgrpunit
    ))
  ) %>%
  select(
    STUDYID,
    USUBJID,
    all_of(trtvar),
    all_of(popfl),
    all_of(subgrpvar),
    subgrpdisplay
  )

adae <- pharmaverseadamjnj::adae %>%
  filter(TRTEMFL == "Y" & AEACN == "DRUG WITHDRAWN") %>%
  select(USUBJID, TRTEMFL, AEBODSYS, AEDECOD)

adsl$colspan_trt <- factor(
  ifelse(adsl[[trtvar]] == "Placebo", " ", "Active Study Agent"),
  levels = c("Active Study Agent", " ")
)

if (risk_diff == TRUE) {
  adsl$rrisk_header <- "Risk Difference (%) (95% CI)"
  adsl$rrisk_label <- paste(adsl[[trtvar]], paste("vs", ctrl_grp))
}

# join data together
ae <- left_join(adsl, adae, by = c("USUBJID"))

colspan_trt_map <- create_colspan_map(
  adsl,
  non_active_grp = ctrl_grp,
  non_active_grp_span_lbl = " ",
  active_grp_span_lbl = "Active Study Agent",
  colspan_var = "colspan_trt",
  trt_var = trtvar
)

# Define layout and build table:

ref_path <- c("colspan_trt", " ", "TRT01A", "Placebo")


extra_args_rr <- list(
  denom = "n_altdf",
  denom_by = "subgrpdisplay",
  riskdiff = FALSE,
  extrablankline = TRUE,
  .stats = c("n_altdf")
)

extra_args_rr2 <- list(
  denom = "n_altdf",
  denom_by = "subgrpdisplay",
  riskdiff = TRUE,
  ref_path = ref_path,
  method = "wald",
  .stats = c("count_unique_fraction")
)

lyt <- basic_table(
  top_level_section_div = " ",
  show_colcounts = TRUE,
  colcount_format = "N=xx"
) %>%
  split_cols_by(
    "colspan_trt",
    split_fun = trim_levels_to_map(map = colspan_trt_map)
  )

if (combined_colspan_trt == TRUE) {
  lyt <- lyt %>%
    split_cols_by(trtvar, split_fun = mysplit)
} else {
  lyt <- lyt %>%
    split_cols_by(trtvar)
}

if (risk_diff == TRUE) {
  lyt <- lyt %>%
    split_cols_by("rrisk_header", nested = FALSE) %>%
    split_cols_by(
      trtvar,
      labels_var = "rrisk_label",
      split_fun = remove_split_levels("Placebo")
    )
}

lyt <- lyt %>%
  split_rows_by(
    "subgrpdisplay",
    split_label = "",
    split_fun = trim_levels_in_group("STUDYID"),
    indent_mod = -1L,
    section_div = c(" "),
    page_by = TRUE
  ) %>% # Set page_by = FALSE if you do not wish to start a new page after a new subgroup
  summarize_row_groups(
    "subgrpdisplay",
    cfun = a_freq_j,
    indent_mod = 0L,
    extra_args = extra_args_rr
  ) %>%
  split_rows_by(
    "TRTEMFL",
    split_fun = keep_split_levels("Y"),
    indent_mod = -1L,
    section_div = c(" ")
  ) %>%
  summarize_row_groups(
    "TRTEMFL",
    cfun = a_freq_j,
    indent_mod = 0L,
    extra_args = append(
      extra_args_rr2,
      list(
        label = "Subjects with >=1 AE leading to discontinuation",
        extrablankline = TRUE
      )
    )
  ) %>%
  split_rows_by(
    "AEBODSYS",
    split_label = "System Organ Class",
    split_fun = trim_levels_in_group("AEDECOD"),
    label_pos = "topleft",
    indent_mod = 0L,
    section_div = c(" ")
  ) %>%
  summarize_row_groups(
    "AEBODSYS",
    cfun = a_freq_j,
    extra_args = extra_args_rr2
  ) %>%
  analyze("AEDECOD", afun = a_freq_j, extra_args = extra_args_rr2) %>%
  append_topleft("  Preferred Term, n (%)")

result <- build_table(lyt, ae, alt_counts_df = adsl)

## Remove the N=xx column headers for the risk difference columns
result <- remove_col_count(result)

# Post-Processing step to sort by descending count on chosen active treatment columns.

if (length(adae$TRTEMFL) != 0) {
  result <- sort_at_path(
    result,
    c("subgrpdisplay", "*", "TRTEMFL", "*", "AEBODSYS"),
    scorefun = jj_complex_scorefun()
  )
  result <- sort_at_path(
    result,
    c("subgrpdisplay", "*", "TRTEMFL", "*", "AEBODSYS", "*", "AEDECOD"),
    scorefun = jj_complex_scorefun()
  )
}

# Add titles and footnotes:

result <- set_titles(result, tab_titles)

# Convert to tbl file and output table

tt_to_tlgrtf(string_map = string_map, tt = result, file = fileid, orientation = "landscape")

TSFAE04a: Subjects With Treatment-emergent Adverse Events Leading to Permanent Discontinuation of Study Treatment by System Organ Class, Preferred Term, and [Subgroup]; Safety Analysis Set (Study jjcs - core)
	Active Study Agent				Risk Difference (%) (95% CI)
System Organ Class	Xanomeline High Dose	Xanomeline Low Dose	Combined	Placebo	Xanomeline High Dose vs Placebo	Xanomeline Low Dose vs Placebo
Preferred Term, n (%)	N=53	N=73	N=126	N=59
Age Group: ≥18 to <65 years	8	5	13	7
Subjects with ≥1 AE leading to  discontinuation	6 (75.0%)	0	6 (46.2%)	1 (14.3%)	60.7 (21.1, 100.0)	-14.3 (-40.2, 11.6)
General disorders and  administration site conditions	2 (25.0%)	0	2 (15.4%)	0	25.0 (-5.0, 55.0)	0.0 (0.0, 0.0)
APPLICATION SITE PRURITUS	2 (25.0%)	0	2 (15.4%)	0	25.0 (-5.0, 55.0)	0.0 (0.0, 0.0)
Skin and subcutaneous tissue  disorders	2 (25.0%)	0	2 (15.4%)	1 (14.3%)	10.7 (-28.9, 50.4)	-14.3 (-40.2, 11.6)
ERYTHEMA	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
PRURITUS	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
DRUG ERUPTION	0	0	0	1 (14.3%)	-14.3 (-40.2, 11.6)	-14.3 (-40.2, 11.6)
Gastrointestinal disorders	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
SALIVARY HYPERSECRETION	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
Infections and infestations	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
UPPER RESPIRATORY TRACT  INFECTION	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
Nervous system disorders	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
HEADACHE	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
Psychiatric disorders	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
LISTLESS	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
Respiratory, thoracic and  mediastinal disorders	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
RESPIRATORY TRACT  CONGESTION	1 (12.5%)	0	1 (7.7%)	0	12.5 (-10.4, 35.4)	0.0 (0.0, 0.0)
Age Group: ≥65 to <75 years	16	17	33	19
Subjects with ≥1 AE leading to  discontinuation	7 (43.8%)	3 (17.6%)	10 (30.3%)	6 (31.6%)	12.2 (-19.9, 44.2)	-13.9 (-41.6, 13.7)
General disorders and  administration site conditions	2 (12.5%)	1 (5.9%)	3 (9.1%)	1 (5.3%)	7.2 (-11.8, 26.3)	0.6 (-14.4, 15.6)
APPLICATION SITE IRRITATION	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
APPLICATION SITE PRURITUS	0	1 (5.9%)	1 (3.0%)	0	0.0 (0.0, 0.0)	5.9 (-5.3, 17.1)
FATIGUE	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
APPLICATION SITE ERYTHEMA	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Skin and subcutaneous tissue  disorders	3 (18.8%)	0	3 (9.1%)	1 (5.3%)	13.5 (-8.1, 35.1)	-5.3 (-15.3, 4.8)
ERYTHEMA	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
PRURITUS	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
RASH	1 (6.2%)	0	1 (3.0%)	1 (5.3%)	1.0 (-14.6, 16.5)	-5.3 (-15.3, 4.8)
SKIN IRRITATION	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
Respiratory, thoracic and  mediastinal disorders	1 (6.2%)	1 (5.9%)	2 (6.1%)	1 (5.3%)	1.0 (-14.6, 16.5)	0.6 (-14.4, 15.6)
ALLERGIC GRANULOMATOUS  ANGIITIS	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
DYSPHONIA	0	1 (5.9%)	1 (3.0%)	0	0.0 (0.0, 0.0)	5.9 (-5.3, 17.1)
NASAL CONGESTION	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
POSTNASAL DRIP	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Gastrointestinal disorders	0	1 (5.9%)	1 (3.0%)	0	0.0 (0.0, 0.0)	5.9 (-5.3, 17.1)
DIARRHOEA	0	1 (5.9%)	1 (3.0%)	0	0.0 (0.0, 0.0)	5.9 (-5.3, 17.1)
VOMITING	0	1 (5.9%)	1 (3.0%)	0	0.0 (0.0, 0.0)	5.9 (-5.3, 17.1)
Investigations	0	1 (5.9%)	1 (3.0%)	2 (10.5%)	-10.5 (-24.3, 3.3)	-4.6 (-22.4, 13.1)
WEIGHT DECREASED	0	1 (5.9%)	1 (3.0%)	0	0.0 (0.0, 0.0)	5.9 (-5.3, 17.1)
BLOOD CREATINE  PHOSPHOKINASE INCREASED	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
ELECTROCARDIOGRAM T WAVE  AMPLITUDE DECREASED	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Vascular disorders	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
WOUND HAEMORRHAGE	1 (6.2%)	0	1 (3.0%)	0	6.2 (-5.6, 18.1)	0.0 (0.0, 0.0)
Metabolism and nutrition  disorders	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
DECREASED APPETITE	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Musculoskeletal and connective  tissue disorders	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
SHOULDER PAIN	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Nervous system disorders	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
PARKINSON'S DISEASE	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Psychiatric disorders	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
DISORIENTATION	0	0	0	1 (5.3%)	-5.3 (-15.3, 4.8)	-5.3 (-15.3, 4.8)
Age Group: ≥75 years	29	51	80	33
Subjects with ≥1 AE leading to  discontinuation	10 (34.5%)	17 (33.3%)	27 (33.8%)	11 (33.3%)	1.1 (-22.5, 24.8)	0.0 (-20.6, 20.6)
General disorders and  administration site conditions	2 (6.9%)	7 (13.7%)	9 (11.2%)	3 (9.1%)	-2.2 (-15.7, 11.3)	4.6 (-9.0, 18.3)
APPLICATION SITE IRRITATION	0	3 (5.9%)	3 (3.8%)	0	0.0 (0.0, 0.0)	5.9 (-0.6, 12.3)
APPLICATION SITE PRURITUS	0	3 (5.9%)	3 (3.8%)	0	0.0 (0.0, 0.0)	5.9 (-0.6, 12.3)
APPLICATION SITE DERMATITIS	1 (3.4%)	0	1 (1.2%)	1 (3.0%)	0.4 (-8.4, 9.3)	-3.0 (-8.9, 2.8)
APPLICATION SITE ERYTHEMA	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
ASTHENIA	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
CHEST PAIN	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
ULCER	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
APPLICATION SITE INDURATION	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
APPLICATION SITE REACTION	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
OEDEMA PERIPHERAL	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Nervous system disorders	3 (10.3%)	4 (7.8%)	7 (8.8%)	0	10.3 (-0.7, 21.4)	7.8 (0.5, 15.2)
DIZZINESS	1 (3.4%)	3 (5.9%)	4 (5.0%)	0	3.4 (-3.2, 10.1)	5.9 (-0.6, 12.3)
SYNCOPE	1 (3.4%)	1 (2.0%)	2 (2.5%)	0	3.4 (-3.2, 10.1)	2.0 (-1.8, 5.8)
HEADACHE	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
Skin and subcutaneous tissue  disorders	2 (6.9%)	3 (5.9%)	5 (6.2%)	3 (9.1%)	-2.2 (-15.7, 11.3)	-3.2 (-15.0, 8.5)
BLISTER	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
PRURITUS	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
RASH	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
RASH PRURITIC	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
SKIN IRRITATION	0	1 (2.0%)	1 (1.2%)	1 (3.0%)	-3.0 (-8.9, 2.8)	-1.1 (-8.0, 5.9)
ERYTHEMA	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
HYPERHIDROSIS	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Cardiac disorders	1 (3.4%)	1 (2.0%)	2 (2.5%)	0	3.4 (-3.2, 10.1)	2.0 (-1.8, 5.8)
MYOCARDIAL INFARCTION	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
PALPITATIONS	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
Infections and infestations	1 (3.4%)	1 (2.0%)	2 (2.5%)	5 (15.2%)	-11.7 (-25.6, 2.2)	-13.2 (-26.0, -0.4)
NASOPHARYNGITIS	1 (3.4%)	1 (2.0%)	2 (2.5%)	1 (3.0%)	0.4 (-8.4, 9.3)	-1.1 (-8.0, 5.9)
LOCALISED INFECTION	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
UPPER RESPIRATORY TRACT  INFECTION	0	0	0	2 (6.1%)	-6.1 (-14.2, 2.1)	-6.1 (-14.2, 2.1)
URINARY TRACT INFECTION	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Injury, poisoning and  procedural complications	1 (3.4%)	1 (2.0%)	2 (2.5%)	0	3.4 (-3.2, 10.1)	2.0 (-1.8, 5.8)
CONTUSION	1 (3.4%)	1 (2.0%)	2 (2.5%)	0	3.4 (-3.2, 10.1)	2.0 (-1.8, 5.8)
Gastrointestinal disorders	0	1 (2.0%)	1 (1.2%)	2 (6.1%)	-6.1 (-14.2, 2.1)	-4.1 (-13.1, 4.9)
DIARRHOEA	0	1 (2.0%)	1 (1.2%)	1 (3.0%)	-3.0 (-8.9, 2.8)	-1.1 (-8.0, 5.9)
HIATUS HERNIA	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Psychiatric disorders	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
DELIRIUM	1 (3.4%)	0	1 (1.2%)	0	3.4 (-3.2, 10.1)	0.0 (0.0, 0.0)
Renal and urinary disorders	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
INCONTINENCE	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
Respiratory, thoracic and  mediastinal disorders	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
DYSPNOEA	0	1 (2.0%)	1 (1.2%)	0	0.0 (0.0, 0.0)	2.0 (-1.8, 5.8)
Eye disorders	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
EYE PRURITUS	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Investigations	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
CYSTOSCOPY	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Surgical and medical  procedures	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
CATARACT OPERATION	0	0	0	1 (3.0%)	-3.0 (-8.9, 2.8)	-3.0 (-8.9, 2.8)
Note: Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.
Note: Adverse events are coded using MedDRA version 26.0.

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